JP2019501143A - Tetrahydroisoquinoline derivatives - Google Patents

Abstract

Disclosed are compounds of formula I and methods of treating viral infections with compositions comprising such compounds. [Selection figure] None

Description

  The present invention relates to substituted tetrahydroisoquinoline compounds, pharmaceutical compositions, and (ii) for inhibiting HIV replication in a subject infected with HIV, or (ii) infected with HIV by administering such compounds. It relates to a method for using them to treat a subject.

  Type 1 human immunodeficiency virus (HIV-1) causes the morbidity of acquired immunodeficiency syndrome (AIDS). The number of HIV cases continues to rise, and now over 25 million individuals worldwide are affected by the virus. Currently, long-term suppression of viral replication by antiretroviral drugs is the only option for treating HIV-1 infection. In fact, the US Food and Drug Administration has approved 25 drugs across 6 different inhibitor classes, which have been shown to significantly improve patient survival and quality of life. However, additional therapies are still needed due to undesired drug-drug interactions, drug-food interactions, failure to treat, and drug resistance due to mutations in the target enzyme.

  Currently, almost all HIV-positive patients are treated with a therapeutic regimen of a combination of antiretroviral drugs, termed highly active antiretroviral therapy (“HAART”). However, in order to avoid the emergence of drug-resistant HIV-1 variants in the short term, HAART therapy is often complicated because different drug combinations must be administered to patients daily. There are many. Although HAART has a positive impact on patient survival, drug resistance may still occur. The emergence of multidrug resistant HIV-1 isolates has serious clinical consequences and must be suppressed by a new drug regimen known as salvage therapy.

  Current guidelines recommend that salvage therapy includes at least two, and preferably three, fully active drugs. The first-line therapy usually combines 3-4 drugs that target the viral enzymes reverse transcriptase and protease. One option for salvage therapy is to administer different combinations of drugs from the same mechanistic class that are still active against resistant isolates. However, the options for this approach are often limited because resistance mutations often result in broad cross-resistance to different drugs of the same class. Recently, the development of fusion inhibitors, entry inhibitors and integrase inhibitors has made alternative treatment strategies available. However, resistance has already been reported in all three new drug classes in both laboratories and patients. Thus, treatment that will result in sustained success in HIV-1 infected patients with antiretroviral drugs will require continued development of new and improved drugs with new targets and mechanisms of action.

  For example, over the last decade, HIV inhibitors have been reported to target protein-protein interactions between HIV-1 integrase and lens epithelial cell-derived growth factor / p75 (“LEDGF”) . LEDGF is a cellular transcriptional cofactor for HIV-1 integrase that promotes viral integration of reverse-transcribed viral cDNA into the host cell genome by linking a pre-integration complex to chromatin. Because of its important role in the early steps of HIV replication, the interaction between LEDGF and integrase is another attractive target for HIV drug therapy.

を有する、ある種のイソインドリン化合物を開示している。 US Provisional Patent Application No. 62 / 027,359 has the following formula:

Certain isoindoline compounds having the following are disclosed:

(式中、
各Yは、独立して、C=O、CH-R⁶又はN-L-R³であり、但し少なくとも1つのYは、CH-R⁶でなければならず、
Xは、O又はCH₂であり、
R¹は、C_1〜6アルキルであり、前記アルキルは、シクロアルキル部分を含有していてもよく、
Wは、結合、-CH=CH-、-C≡C-、C_1〜3アルキレン、-CH₂C(O)NH-、-NHC(O)-、-N(CH₃)C(O)-、-N(CH₃)C(O)CH₂-、-C(O)-、-CH₂(CO)-又は-NHC(O)CH₂-であり、各Wは、1つ又は2つのメチル基により場合により置換されており、
R²は、H、C_1〜6アルキル、C_5〜14アリール、C_3〜7シクロアルキル、C_3〜7シクロアルケニル、C_3〜9複素環又はC_5〜9ヘテロアリールであり、ここで、各R²基は、ハロ、C_1〜6アルキル、C_1〜6ヘテロアルキル又はC_1〜6アルキレン又はC_1〜6ヘテロアルキレンから選択される1〜4つの置換基により場合により置換されており、前記C_1〜6アルキレン又はC_1〜6ヘテロアルキレンは、前記C_5〜14アリール、C_3〜7シクロアルキル、C_3〜7シクロアルケニル、C_3〜9複素環又はC_5〜9ヘテロアリール上の隣接する炭素原子に結合して、縮合環を形成し、
各Lは、独立して、結合、-CH₂(CO)-、-C_1〜3アルキレン-、-SO₂-、-C(O)-、-C(S)-、-C(NH)-、-C(O)NH-、-C(O)NHCH₂-、-C(O)N-、-C(O)OCH₂-、-C(O)O-、-C(O)C(O)-、-SO₂-NH-又は-CH₂C(O)-であり、
各R³は、独立して、H、CN、オキソ、C_1〜6アルキル、C_5〜14アリール、CH₂C_5〜14アリール、CH₂C_3〜7シクロアルキル、C_3〜7シクロアルキル、C_3〜7スピロシクロアルキル、C_3〜7シクロアルケニル、C_3〜9複素環若しくはC_5〜9ヘテロアリールであるか、又はR³は、R⁶又はR³と一緒になって縮合5〜7員環を形成してもよく、各R³基は、ハロ、オキソ、C_1〜6アルキル、C_3〜7シクロアルキル、C_1〜3フルオロアルキル、-OC_1〜6アルキル、-C(O)R⁴、-C(O)NR⁴、-C(O)NHR⁴、C_5〜14アリール、C_1〜6ヘテロアルキル、-B(OH)₂、C_3〜9複素環、C_5〜9ヘテロアリール、-C(O)OC_1〜6アルキルから選択される1〜4つの置換基により場合により置換されているか、又は2つの置換基は一緒に結合して、縮合環、スピロ環若しくは架橋環を形成してもよく、この縮合環、スピロ環又は架橋環は、R⁴により場合により置換されていてもよく、
R⁴は、CN、ハロ、-OC_1〜6アルキル、C_1〜6アルキル、C_3〜7シクロアルキル、C_3〜9複素環又はC_5〜14アリールであり、
各R⁵は、独立して、H、C_1〜3アルキル、C_3〜6シクロアルキル、CH₂F、CHF₂又はCF₃であり、
各R⁶は、独立して、H、オキソ、C_1〜3アルキル、C_5〜14アリール、C_3〜9複素環、C_5〜9ヘテロアリール、-C(O)NR⁴若しくは-C(O)NHR⁴であるか、又はR⁶の両方は一緒になって2〜4個の炭素原子を含み、一緒になって架橋環系を形成してもよく、又はR⁶は、ジェミナルな(gem)ジ-C_1〜3アルキルを表してもよく、
複素環、ヘテロアリール、ヘテロアルキル及びヘテロアルキレンは、それぞれ、S、N、B又はOから選択される1〜3個のヘテロ原子を含む)
を開示している。 Briefly, in one aspect, the invention provides a compound of formula I:

(Where
Each Y is independently C═O, CH—R ⁶ or NLR ³ , provided that at least one Y must be CH—R ⁶ ;
X is O or CH ₂
R ¹ is C _1-6 alkyl, which alkyl may contain a cycloalkyl moiety,
W is a bond, —CH═CH—, —C≡C—, C _1-3 alkylene, —CH ₂ C (O) NH—, —NHC (O) —, —N (CH ₃ ) C (O) -, -N (CH ₃ ) C (O) CH _2- , -C (O)-, -CH ₂ (CO)-or -NHC (O) CH _2- , wherein each W is 1 or 2 Optionally substituted by two methyl groups,
R ² is H, C _1-6 alkyl, C _5-14 aryl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _3-9 heterocycle or C _5-9 heteroaryl, wherein Each R ² group is optionally substituted with 1 to 4 substituents selected from halo, C _1-6 alkyl, C _1-6 heteroalkyl or C _1-6 alkylene or C _1-6 heteroalkylene. The C _1-6 alkylene or C _1-6 heteroalkylene is the C _5-14 aryl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _3-9 heterocycle or C _5-9 heterocycle. Bonded to adjacent carbon atoms on the aryl to form a fused ring;
Each L is independently a _{bond, -CH 2 (CO) -,} - C 1~3 alkylene _{-, - SO 2 -, -} C (O) -, - C (S) -, - C (NH) -, -C (O) NH-, -C (O) NHCH _2- , -C (O) N-, -C (O) OCH _2- , -C (O) O-, -C (O) C (O)-, -SO ₂ -NH- or -CH ₂ C (O)-,
Each R ³ is independently H, CN, oxo, C _1-6 alkyl, C _5-14 aryl, CH ₂ C _5-14 aryl, CH ₂ C _3-7 cycloalkyl, C _3-7 cycloalkyl , C _3-7 spirocycloalkyl, C _3-7 cycloalkenyl, C _3-9 heterocycle or C _5-9 heteroaryl, or R ³ is fused together with R ⁶ or R ³ ~ 7 membered ring may be formed, each R ³ group is halo, oxo, C _1-6 alkyl, C _3-7 cycloalkyl, C _1-3 fluoroalkyl, -OC _1-6 alkyl, -C (O) R ⁴ , -C (O) NR ⁴ , -C (O) NHR ⁴ , C _5-14 aryl, C _1-6 heteroalkyl, -B (OH) ₂ , C _3-9 heterocycle, C Optionally substituted by 1 to 4 substituents selected from _5-9 heteroaryl, -C (O) OC _1-6 alkyl, or the two substituents are joined together to form a fused ring, spiro A ring or a bridged ring may be formed, and this condensed ring, spiro ring or Bridged ring may optionally be replaced by R ^4,
R ⁴ is CN, halo, —OC _1-6 alkyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-9 heterocycle or C _5-14 aryl,
Each R ⁵ is independently H, C _1-3 alkyl, C _3-6 cycloalkyl, CH ₂ F, CHF ₂ or CF ₃ ;
Each R ⁶ is independently H, oxo, C _1-3 alkyl, C _5-14 aryl, C _3-9 heterocycle, C _5-9 heteroaryl, —C (O) NR ⁴ or —C ( O) NHR ⁴ or both R ⁶ together may contain 2 to 4 carbon atoms and together form a bridged ring system or R ⁶ is geminal ( gem) may represent di-C _1-3 alkyl,
(Heterocycle, heteroaryl, heteroalkyl and heteroalkylene each contain 1 to 3 heteroatoms selected from S, N, B or O)
Is disclosed.

  In another aspect, the present invention discloses pharmaceutically acceptable salts of compounds of formula I.

  In another aspect, the invention discloses a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

  In another aspect, the invention provides a method of treating a viral infection in a patient that is at least partially mediated by a virus in the retroviral family of viruses, wherein the patient is treated with a compound of formula I or a pharmaceutically acceptable And a method comprising administering a composition comprising the salt thereof. In some embodiments, the viral infection is mediated by HIV virus.

  In another aspect, certain embodiments of the invention provide a method of treating a subject infected with HIV, wherein the subject is treated with a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. A method comprising the step of administering is provided.

  In yet another aspect, certain embodiments of the invention are methods of inhibiting the progression of HIV infection in a subject at risk of being infected with HIV, wherein the subject is treated with a therapeutically effective amount of a compound of formula I or pharmacy Administering a pharmaceutically acceptable salt thereof. These and other embodiments are further described in the text that follows.

  According to another embodiment of the invention, there is provided a method of preventing or treating a viral infection mediated at least in part by a virus in a retroviral family of viruses in a mammal, said method comprising said viral infection. Administering a compound defined in Formula I to a mammal diagnosed with or at risk of developing the viral infection, wherein the virus is an HIV virus, and the method further comprises Administering one or more agents active against HIV virus, said agent active against HIV virus comprising: a nucleotide reverse transcriptase inhibitor; a non-nucleotide reverse transcriptase inhibitor; Protease inhibitors; entry inhibitors, adhesion inhibitors and fusion inhibitors; integrase inhibitors; maturation inhibitors; CXCR4 inhibitors; and CCR5 inhibitors It is selected from the group consisting of.

  Preferably W is a bond.

Preferably one of Y is NLR ³ .

Preferably R ¹ is C _1-6 alkyl. Most preferably R ¹ is t-butyl.

  Preferably X is O.

Preferably R ² is optionally substituted phenyl. Most preferably, R ² is fluorine, methyl, —CH ₂ CH ₂ CH ₂ O—, wherein the —CH ₂ CH ₂ CH ₂ O— is bonded to the adjacent carbon atom on the phenyl and Form a cyclic ring), or -NHCH ₂ CH ₂ O- (wherein the -NHCH ₂ CH ₂ O- is bonded to an adjacent carbon atom on the phenyl to form a bicyclic ring) Phenyl substituted by 1 to 4 substituents selected from

Preferably, each R ³ is independently C _1-6 alkyl, phenyl, naphthyl, cyclopentyl, cyclohexyl, pyridyl or tetrahydropyranyl, each of which is halogen, C _1-6 alkyl, —OC ₁ optionally substituted ₆ alkyl, by one to three substituents selected from C _1-3 fluoroalkyl or phenyl.

Preferably each R ⁵ is methyl.

Preferably each R ⁶ is H.

Preferably, the stereochemistry on the carbon to which XR ¹ is attached is as illustrated below.

  “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts derived from various organic and inorganic counterions well known in the art, and by way of example only sodium, potassium, calcium, magnesium Organic compounds such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate and oxalate if the molecule contains basic functional groups, including ammonium and tetraalkylammonium Includes salts of acids or inorganic acids. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use, 2002.

  The compounds of this invention can be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and specific compounds of the invention are prepared in the examples.

  The following examples serve to more fully illustrate how to make and use the above invention. It should be understood that these examples do not serve in any way to limit the true scope of the invention, but are rather shown for illustrative purposes. In the examples below and the synthetic schemes above, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

aq. = aqueous solution μL = microliter μM = micromolar concentration
NMR = Nuclear magnetic resonance
BINAP = (2,2'-bis (diphenylphosphino) -1,1'-binaphthyl)
boc = tert-butoxycarbonyl
br = wide
Cbz = benzyloxycarbonyl
d = double line δ = chemical shift ° C = degrees Celsius
DCE = 1,2-dichloroethane
DCM = dichloromethane
dd = double double wire
DIEA = N, N-diisopropylethylamine
DMEM = Dulbecco's Modified Eagle Medium
DMF = N, N-dimethylformamide
DMSO = dimethyl sulfoxide
EtOAc = ethyl acetate
g = grams
h or hr = hour
HCV = Hepatitis C virus
HPLC = high performance liquid chromatography
Hz = Hertz
IU = international unit
IC ₅₀ = inhibitory concentration at 50% inhibition
J = coupling constant (given in Hz unless otherwise indicated)
m = Multiple line
M = Molar concentration
M + H ⁺ = parent mass spectral peak + H +
mg = milligram
min = minutes
mL = milliliter
mM = mmol concentration
mmol = mmol
MS = mass spectrum
nm = nanomolar concentration
ppm = parts per million
qs = sufficient amount
s = single line
RT = room temperature
sat. = saturation
t = triple line
THF = tetrahydrofuran
TFA = trifluoroacetic acid
TMS = trimethylsilyl
T3P = propyl phosphonic anhydride
TFA = trifluoroacetic acid
Z = benzyloxycarbonyl

[Example 1]
2- (tert-Butoxy) -2- (2- (3-fluorobenzyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetic acid

Step 1: benzyl 5,8-dimethyl-6-oxo-3,4,6,7,8,8a-hexahydroisoquinoline-2 (1H) -carboxylate

A solution of benzyl 4-oxopiperidine-1-carboxylate (25 g, 107 mmol) and pyrrolidine (44.3 mL, 536 mmol) in toluene (60 mL) was refluxed for 48 hours using a Dean-Stark trap. Toluene was azeotroped using toluene to remove the solvent. The amber oil was redissolved in toluene (60 mL) and (E) -hex-4-en-3-one (12.26 mL, 107 mmol) and hydroquinone (0.118 g, 1.072 mmol) were added. The solution was heated to reflux, stirred overnight, cooled to room temperature, diluted with EtOAc and 1M HCl, extracted with EtOAc, dried over Na ₂ SO ₄ and the solvent removed. The brown oil was purified by silica gel chromatography (0-100% EtOAc / hexanes gradient elution) to give the title compound as a yellow oil (23.25 g, 74.2 mmol, 69.2% yield). LCMS (ES +) (m / z): 314.28 (M + 1).

Step 2: benzyl 6-hydroxy-5,8-dimethyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate

To a solution of benzyl 5,8-dimethyl-6-oxo-1,4,4a, 5,6,8a-hexahydroisoquinoline-2 (3H) -carboxylate (12.37 g, 39.5 mmol) in THF (60 mL), At 78 ° C. LHMDS (53.1 mL, 53.1 mmol) was added dropwise. The solution was stirred for 30 minutes and then TMSCl (6.05 mL, 47.4 mmol) was added dropwise. The solution was stirred for 2 hours, then warmed to room temperature, stirred for 15 minutes, diluted with di-ethyl ether, poured onto ice and NaHCO ₃ and extracted with diethyl ether. The solution was concentrated, dissolved in acetonitrile (300 mL) and palladium (II) acetate (18.32 g, 82 mmol) was added. The suspension was stirred overnight and the color change was observed. The color changed from brown without turbidity to black with turbidity. The solution was filtered over celite to remove the solvent. The brown oil was redissolved in EtOAc (300 mL) and TBAF (148 mL, 148 mmol) was added dropwise. The solution was stirred for 2 h, then diluted with H ₂ O, EtOAc and 1M HCl, extracted with EtOAc, dried over Na ₂ SO ₄ and the solvent removed. The brown oil was purified by silica gel chromatography (0-30% EtOAc / hexanes gradient elution) to give the title compound as a white solid (10.3 g, 33.1 mmol, 44.6% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.29 (m, 5H), 6.53 (s, 1H), 5.20 (s, 2H), 4.70 (s, 1H), 4.49 (s, 2H), 3.73 ( m, 2H), 2.74 (m, 2H), 2.23-2.05 (m, 6H). LCMS (ES +) (m / z): 312.27 (M + 1); 334.30 (M + 23).

Step 3: benzyl 7-bromo-6-hydroxy-5,8-dimethyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate

To a solution of benzyl 6-hydroxy-5,8-dimethyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate (4 g, 12.85 mmol) in DCM (250 mL), sodium bicarbonate (1.403 g, 16.70 mmol), NBS (2.52 g, 14.13 mmol) was then added. A color change was observed from off-white to yellow. The solution was stirred for 30 minutes, then diluted with DCM and 10% sodium thiosulfate, extracted with DCM, dried over Na ₂ SO ₄ and the solvent removed. The yellow foam was purified by silica gel chromatography (gradient elution with 0-20% EtOAc / hexanes) to give the title compound as an off-white solid (4.15 g, 10.63 mmol, 83% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.29 (m, 5H), 5.64 (s, 1H), 5.19 (s, 2H), 4.53 (s, 2H), 3.71 (m, 2H), 2.72 ( m, 2H), 2.41-2.11 (m, 6H) .LCMS (ES +) (m / z): 390.34 (M + 1); 412.23 (M + 23); 801.34 (2M + 23).

Step 4: benzyl 6-hydroxy-5,8-dimethyl-7-vinyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate

A solution of benzyl 7-bromo-6-hydroxy-5,8-dimethyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate (6.82 g, 17.48 mmol) in 1-propanol (170 mL) was degassed for 10 minutes. . Vinyl trifluoroborate (9.36 g, 69.9 mmol), TEA (17.05 mL, 122 mmol) and PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (1.613 g, 1.975 mmol) were added and the solution was refluxed at 130 ° C. for 1 hour. did. The solution was cooled to room temperature, diluted with EtOAc and water, extracted with EtOAc, dried over Na ₂ SO ₄ and the solvent removed. The brown oil was purified by silica gel chromatography (0-100% EtOAc / hexanes gradient elution) to give the title compound as a yellow oil (4.776 g, 14.15 mmol, 81% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.29 (m, 5H), 6.71 (m, 1H), 5.75 (m, 1H), 5.64 (s, 1H), 5.50 (m, 2H), 5.19 ( s, 2H), 4.51 (s, 2H), 3.72 (m, 2H), 2.75 (m, 2H), 2.22-2.01 (m, 6H) .LCMS (ES +) (m / z): 338.41 (M + 1 ); 360.36 (M + 23); 697.56 (2M + 23).

Step 5: Benzyl 5,8-dimethyl-6-(((trifluoromethyl) sulfonyl) oxy) -7-vinyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate

To a solution of benzyl 6-hydroxy-5,8-dimethyl-7-vinyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate (4.776 g, 14.15 mmol) in DMF (50 mL) was added K ₂ CO ₃ (3.91 g, 28.3 mmol) followed by PhNTf ₂ (10.62 g, 29.7 mmol). The suspension was stirred for 1 hour, diluted with di-ethyl ether and water, extracted with di-ethyl ether, dried over Na ₂ SO ₄ and the solvent removed. The resulting yellow oil was purified by silica gel chromatography (0-20% EtOAc / hexanes gradient elution) to give the title compound as a hazy oil (5.54 g, 11.80 mmol, 83% yield). ). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.29 (m, 5H), 6.66 (m, 1H), 5.68 (m, 1H), 5.37 (m, 1H), 5.20 (s, 2H), 4.56 ( s, 2H), 3.75 (m, 2H), 2.76 (m, 2H), 2.33-2.12 (m, 6H). LCMS (ES +) (m / z): 470.28 (M + 1); 492.28 (M + 23).

Step 6: Benzyl 5,8-dimethyl-6- (p-tolyl) -7-vinyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate

Benzyl 5,8-dimethyl-6-(((trifluoromethyl) sulfonyl) oxy) -7-vinyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate (1.84 g, 3.92 mmol), p-tolylboron A solution of acid (1.332 g, 9.80 mmol) in DMF (12 mL) was degassed for 5 minutes. Pd (PPh ₃ ) ₄ (0.906 g, 0.784 mmol) and Na ₂ CO ₃ (5.88 ml, 11.76 mmol) were added and then the solution was heated to 120 ° C. in the microwave with stirring for 30 minutes. The solution was diluted with diethyl ether and water, extracted with diethyl ether, washed with brine, dried over Na ₂ SO ₄ and the solvent removed. The resulting oil was purified by silica gel chromatography (0-100% EtOAc / hexanes gradient elution) to give the title compound as a yellow oil (1.34 g, 3.26 mmol, 83% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.29 (m, 5H), 7.18 (m, 2H), 6.96 (m, 2H), 6.32 (m, 1H), 5.28-5.16 (m, 3H), 4.94 (m, 1H), 4.65 (s, 2H), 3.79 (m, 2H), 2.80 (m, 2H), 2.40 (s, 3H), 2.28 (s, 3H), 1.91 (s, 3H). LCMS (ES +) (m / z): 412.35 (M + 1); 434.35 (M + 23).

Step 7: benzyl 7-formyl-5,8-dimethyl-6- (p-tolyl) -3,4-dihydroisoquinoline-2 (1H) -carboxylate

Benzyl 5,8-dimethyl-6- (p-tolyl) -7-vinyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate (4 g, 9.72 mmol) in THF / H ₂ O (3: 1, To the solution, potassium osmate dihydrate (1.074 g, 2.92 mmol) was added followed by sodium periodate (12.47 g, 58.3 mmol). The solution was stirred for 1 hour, diluted with EtOAc and 10% sodium thiosulfate, extracted with EtOAc, dried over Na ₂ SO ₄ and the solvent removed. The resulting oil was purified by silica gel chromatography (gradient elution with 0-20% EtOAc / hexanes) to give the title compound as a white solid (1.81 g, 4.38 mmol, 45.0% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.73 (s, 1H), 7.44-7.31 (m, 5H), 7.24 (m, 2H), 7.04 (m, 2H), 5.22 (s, 2H), 4.68 ( s, 2H), 3.78 (m, 2H), 2.84 (m, 2H), 2.54-2.37 (m, 6H), 1.96 (s, 3H). LCMS (ES +) (m / z): 414.44 (M + 1 ); 436.43 (M + 23); 827.60 (2M + 1).

Step 8: benzyl 7- (cyano ((trimethylsilyl) oxy) methyl) -5,8-dimethyl-6- (p-tolyl) -3,4-dihydroisoquinoline-2 (1H) -carboxylate

To a solution of benzyl 7-formyl-5,8-dimethyl-6- (p-tolyl) -3,4-dihydroisoquinoline-2 (1H) -carboxylate (1.81 g, 4.38 mmol) in DCM (35 mL) at 0 ° C. Zinc iodide (0.699 g, 2.189 mmol) was added followed by TMS-CN (5.87 mL, 43.8 mmol). The solution was stirred for 1 hour, diluted with DCM, poured onto ice, extracted with DCM, dried over Na ₂ SO ₄ and the solvent removed. The resulting yellow oil was subjected to the next step without further purification.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.21 (m, 7H), 7.01 (m, 2H), 5.35 (s, 1H), 5.21 (s, 2H), 4.65 (s, 2H), 3.76 ( m, 2H), 2.78 (m, 2H), 2.58-2.37 (m, 6H), 1.87 (s, 3H), 0.00 (s, 9H) .LCMS (ES +) (m / z): 513.37 (M + 1 ); 535.49 (M + 23); 1026.18 (2M + 1).

Step 9: methyl 2- (5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2-hydroxyacetate

HCl gas was bubbled into MeOH for 20 minutes at 0 ° C. to make a saturated HCl solution. This solution (200 mL) was added at 0 ° C. to benzyl 7- (cyano ((trimethylsilyl) oxy) methyl) -5,8-dimethyl-6- (p-tolyl) -3,4-dihydroisoquinoline-2 (1H)- To a flask containing carboxylate (2.29 g, 4.47 mmol) was added. Stir the solution at 0 ° C. for 5 minutes, warm to room temperature, stir for 2 hours, cool and return to 0 ° C., blow HCl into the solution for 1 hour, stir at 0 ° C. for 1 hour, warm to room temperature And stirred for 1 hour. MeOH was removed by rotary evaporation without being immersed in a water bath. The resulting turbid oil was suspended in 1M HCl (150 mL), heated to 90 ° C. for 2.5 hours, poured onto ice / water, neutralized with 50% NaOH and 1M NaOH, 1: 3 Extracted with IPA / CHCl ₃ , solvent removed and the colorless oil free of turbidity was subjected to the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (m, 1H), 7.22 (m, 2H), 7.09 (m, 1H), 5.08 (s, 1H), 4.71 (s, 1H), 3.96 (s, 2H), 3.70 (s, 3H), 3.15 (m, 2H), 2.68 (m, 2H), 2.41 (s, 3H), 2.11 (s, 3H), 1.86 (s, 3H) .LCMS (ES +) ( m / z): 340.47 (M + 1); 679.65 (2M + 1).

Step 10: methyl 2- (tert-butoxy) -2- (5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetate

Methyl 2- (5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2-hydroxyacetate (330 mg, 0.972 mmol) tert-butyl acetate ( To a solution (50 mL, 370 mmol) was added perchloric acid (1 mL, 16.62 mmol). The solution is stirred for 30 minutes, then diluted with EtOAc and water, basified with 1M NaOH and 50% NaOH, extracted with EtOAc, washed with brine, dried over Na ₂ SO ₄ and the solvent removed. Removed. The tan solid was purified by silica gel chromatography (0-10% MeOH / DCM gradient elution) to give the title compound as a white solid (700 mg, 1.770 mmol, 41.1% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 (m, 3H), 7.05 (m, 1H), 5.03 (s, 1H), 4.00 (s, 2H), 3.67 (s, 3H), 3.20 (m, 2H), 2.71 (m, 2H), 2.43 (s, 3H), 2.23 (s, 3H), 1.84 (s, 3H), 0.95 (s, 9H) .LCMS (ES +) (m / z): 396.44 ( M + 1); 791.69 (2M + 1).

Step 11: methyl 2- (tert-butoxy) -2- (2- (3-fluorobenzyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-7 -Ill) Acetate

DCE of methyl 2- (tert-butoxy) -2- (5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetate (20 mg, 0.051 mmol) To the (2 mL) solution, 3-fluorobenzaldehyde (8.05 μl, 0.076 mmol) was added. The solution was stirred for 10 minutes and then sodium triacetoxyborohydride (16.92 mg, 0.076 mmol) was added. After 30 minutes, sodium triacetoxyborohydride (5.64mg, 0.025mmol) was added and the solution was stirred for 30 min, diluted with DCM and. NaHCO _3, extracted with DCM, and dried over Na ₂ SO _4, The solvent was removed. The purple oil was subjected to the next step without further purification.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-6.92 (m, 8H), 5.02 (s, 1H), 3.74 (s, 2H), 3.65 (s, 3H), 3.60 (s, 2H), 2.82- 2.63 (m, 4H), 2.42 (s, 3H), 2.19 (s, 3H), 1.83 (s, 3H), 0.94 (s, 9H) .LCMS (ES +) (m / z): 504.51 (M + 1 ); 526.45 (2M + 1).

Step 12: 2- (tert-butoxy) -2- (2- (3-fluorobenzyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-7- Yl) acetic acid

Methyl 2- (tert-butoxy) -2- (2- (3-fluorobenzyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) To a solution of acetate (25 mg, 0.050 mmol) in 1,4-dioxane (4 mL) was added LiOH (0.745 mL, 0.745 mmol). The solution was stirred at 70 ° C. overnight. The solution was concentrated, EtOAc was added, washed with 1M HCl, brine, the solvent was removed and the oil was purified by reverse phase HPLC to give the title compound as a white solid (13.2 mg, 0.027 mmol, 54.3 %yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (m, 1H), 7.39-7.15 (m, 6H), 7.08 (m, 1H), 5.15 (s, 1H), 4.72-2.84 (m, 8H), 2.42 (s, 3H), 2.11 (s, 3H), 1.90 (s, 3H), 0.98 (s, 9H) .LCMS (ES +) (m / z): 490.70 (M + 1); 979.86 (2M + 1 ).

[Example 2]
2- (tert-Butoxy) -2- (2-cyclohexyl-5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetic acid

The title compound was made from cyclohexanone in a manner similar to that described in Example 1 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.08 (m, 4H), 5.15 (s, 1H), 4.53 (m, 1H), 4.09 (m, 1H), 3.74 (m, 1H), 3.47- 3.13 (m, 3H), 2.92 (m, 1H), 2.42 (s, 3H), 2.30-2.14 (m, 5H), 2.00 (m, 2H), 1.90 (s, 3H), 1.83-1.56 (m, 2H), 1.50-1.19 (m, 4H), 0.98 (s, 9H) .LCMS (ES +) (m / z): 464.51 (M + 1).

[Example 3]
2- (tert-Butoxy) -2- (2- (cyclohexylmethyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetic acid

The title compound was made from cyclohexanecarbaldehyde in a manner similar to that described in Example 1 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 (m, 1H), 7.26 (m, 2H), 7.09 (m, 1H), 5.16 (m, 1H), 4.72 (m, 1H), 3.99-3.76 ( m, 1H), 3.25-2.82 (m, 3H), 2.43 (s, 3H), 2.18 (s, 3H), 1.99-1.66 (m, 9H), 1.39-1.05 (m, 8H), 0.97 (s, 9H) .LCMS (ES +) (m / z): 479.49 (M + 1); 955.95 (2M + 1).

[Example 4]
2- (tert-Butoxy) -2- (2- (cyclohexanecarbonyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetic acid

Step 1: methyl 2- (tert-butoxy) -2- (2- (cyclohexanecarbonyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl )acetate

To a solution of cyclohexanecarbonyl chloride (0.034 mL, 0.253 mmol) in DCM (2 mL) is added TEA (0.042 mL, 0.303 mmol), then methyl 2- (tert-butoxy) -2- (5,8-dimethyl-6- (p -Tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetate (20 mg, 0.051 mmol) in DCM (1 mL) was added. The solution was stirred for 24 hours, diluted with DCM and 1M HCl, washed with brine and the solvent removed. The resulting oil was purified by silica gel chromatography (0-100% EtOAc / hexanes gradient elution) to give the title compound as a white solid (12.5 mg, 0.025 mmol, 48.9% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 (m, 3H), 7.05 (m, 1H), 5.04 (s, 1H), 4.66 (m, 2H), 4.04-3.59 (m, 5H), 2, 87-2.54 (m, 3H), 2.42 (s, 3H), 2.30 (s, 3H), 1.94-1.20 (m, 13H), 0.97 (s, 9H) .LCMS (ES +) (m / z): 506.56 (M + 1); 1012.00 (2M + 1).

Step 2: 2- (tert-butoxy) -2- (2- (cyclohexanecarbonyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) Acetic acid

Methyl 2- (tert-butoxy) -2- (2- (cyclohexanecarbonyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetate ( To a solution of 12.5 mg, 0.025 mmol) in 1,4-dioxane (2 mL) was added KOTMS (12.68 mg, 0.099 mmol). The solution was heated to 100 ° C. and stirred for 2 h, then diluted with EtOAc and 1M HCl, extracted with EtOAc, dried over Na ₂ SO ₄ and the solvent removed. The resulting brown oil was purified by reverse phase HPLC to give the title compound as a white solid (6.4 mg, 0.013 mmol, 52.7% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36 (m, 1H), 7.23 (m, 2H), 7.07 (m, 1H), 5.18 (m, 1H), 4.89 (m, 1H), 4.63-4.43 ( m, 1H), 3.99-3.59 (m, 1H), 2.87-2.69 (m, 2H), 2.61 (m, 1H), 2.42 (s, 3H), 2.23 (s, 3H), 1.93-1.67 (m, 9H), 1.67-1.49 (m, 2H), 1.31 (m, 3H), 0.98 (s, 9H) .LCMS (ES +) (m / z): 492.57 (M + 1); 984.02 (2M + 1).

[Example 5]
2- (tert-butoxy) -2- (5,8-dimethyl-2- (2-oxo-2- (piperidin-1-yl) acetyl) -6- (p-tolyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) acetic acid

Step 1: methyl 2- (tert-butoxy) -2- (5,8-dimethyl-2- (2-oxo-2- (piperidin-1-yl) acetyl) -6- (p-tolyl) -1, 2,3,4-Tetrahydroisoquinolin-7-yl) acetate

To a solution of 2-oxo-2- (piperidin-1-yl) acetic acid (15.89 mg, 0.101 mmol) in EtOAc (1 mL) was added TEA (0.021 mL, 0.152 mmol) and T3P (0.075 mL, 0.126 mmol). The solution is stirred for 10 minutes and then methyl 2- (tert-butoxy) -2- (5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl ) Acetate (20 mg, 0.051 mmol) was added. The reaction was stirred at room temperature overnight, diluted with EtOAc and NaHCO ₃ and washed with brine to remove the solvent. The purple oil was subjected to the next step without further purification.
¹ H NMR (400 MHz, CDCl ₃ ) δ (mixture of rotamers) 7.22 (m, 3H), 7.05 (m, 1H), 5.03 (m, 1H), 4.81-4.42 (m, 2H), 3.80- 3.57 (m, 6H), 3.41 (m, 2H), 2.83 (m, 2H), 2.42 (m, 3H), 2.35-2.18 (m, 3H), 1.86 (m, 3H), 1.77-1.55 (m, 6H), 0.95 (m, 9H) .LCMS (ES +) (m / z): 557.57 (M + 23); 1070.02 (2M + 1).

Step 2: 2- (tert-butoxy) -2- (5,8-dimethyl-2- (2-oxo-2- (piperidin-1-yl) acetyl) -6- (p-tolyl) -1,2 , 3,4-Tetrahydroisoquinolin-7-yl) acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ (mixture of rotamers) 7.33 (m, 1H), 7.23 (m, 2H), 7.06 (m, 1H), 5.16 (m, 1H), 4.90-4.40 ( m, 2H), 4.05-3.16 (m, 6H), 2.83 (m, 2H), 2.42 (m, 3H), 2.30-2.13 (m, 3H), 1.88 (m, 3H), 1.67 (m, 7H) , 0.98 (m, 9H) .LCMS (ES +) (m / z): 521.51 (M + 1); 543.44 (M + 23); 1041.98 (2M + 1).

[Example 6]
2- (tert-Butoxy) -2- (2- (3-fluorobenzyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetic acid

The title compound was made from 3-fluorobenzoic acid in a manner similar to that described in Example 5 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ (mixture of rotamers) 7.59-6.85 (m, 8H), 5.15 (br. S., 1H), 4.93 (m, 1H), 4.56 (m, 1H) , 3.99 (m, 1H), 3.76-3.43 (m, 1H), 3.21 (m, 1H), 2.90-2.66 (m, 2H), 2.40 (s, 3H), 2.28 (br.s., 2H), 1.99 (m, 1H), 1.87 (s, 3H), 0.98 (s, 9H) LCMS (ES +) (m / z): 504.34 (M + 1).

[Example 7]
2- (tert-butoxy) -2- (5,8-dimethyl-2- (2-oxo-2- (piperidin-1-yl) ethyl) -6- (p-tolyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) acetic acid

Step 1: methyl 2- (tert-butoxy) -2- (2- (2-methoxy-2-oxoethyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydro Isoquinolin-7-yl) acetate

DMF of methyl 2- (tert-butoxy) -2- (5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetate (10 mg, 0.025 mmol) To the (2 mL) solution was added methyl 2-bromoacetate (4.31 μl, 0.046 mmol) and cesium carbonate (12.36 mg, 0.038 mmol). The solution was stirred overnight at room temperature, diluted with diethyl ether and water, extracted with diethyl ether, dried over Na ₂ SO ₄ and the solvent removed. The resulting oil was purified by silica gel chromatography (0-20% EtOAc / hexanes gradient elution) to give the title compound as a white solid (11.4 mg, 0.024 mmol, 96% yield).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20 (m, 3H), 7.04 (m, 1H), 5.01 (s, 1H), 3.89-3.58 (m, 8H), 3.49 (s, 2H), 2.96- 2.75 (m, 4H), 2.42 (s, 3H), 2.21 (s, 3H), 1.82 (s, 3H), 0.94 (s, 9H). LCMS (ES +) (m / z): 468.50 (M + 1 ); 935.87 (2M + 1).

Step 2: 2- (7- (1- (tert-butoxy) -2-methoxy-2-oxoethyl) -5,8-dimethyl-6- (p-tolyl) -3,4-dihydroisoquinoline-2 (1H ) -Yl) acetic acid

Methyl 2- (tert-butoxy) -2- (2- (2-methoxy-2-oxoethyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-7 To a solution of -yl) acetate (11.6 mg, 0.025 mmol) in 1,4-dioxane (2 mL), LiOH (0.099 mL, 0.099 mmol) was added and the solution was stirred at room temperature for 1 h and additional LiOH (0.099 mL, 0.099 mmol). mmol) was added and stirred for 1 h, diluted with 1M HCl, extracted with EtOAc, washed with brine and the solvent removed. The resulting oil was purified by silica gel chromatography (gradient elution from 0-20% MeOH / DCM) to give the title compound as a turbid oil (8 mg, 0.018 mmol, 71.1% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24-7.09 (m, 3H), 7.02 (m, 1H), 4.99 (s, 1H), 4.38 (m, 2H), 3.92 (m, 2H), 3.74- 3.34 (m, 5H), 3.00 (m, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 1.83 (s, 3H), 0.92 (s, 9H) .LCMS (ES +) (m / z ): 454.49 (M + 1); 907.83 (2M + 1).

Step 3: Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-2- (2-oxo-2- (piperidin-1-yl) ethyl) -6- (p-tolyl) -1, 2,3,4-Tetrahydroisoquinolin-7-yl) acetate

2- (7- (1- (tert-butoxy) -2-methoxy-2-oxoethyl) -5,8-dimethyl-6- (p-tolyl) -3,4-dihydroisoquinolin-2 (1H) -yl Piperidine (10.89 μl, 0.110 mmol) was added to a solution of acetic acid (25 mg, 0.055 mmol), TEA (0.023 mL, 0.165 mmol) and T3P (0.082 mL, 0.138 mmol) in EtOAc (1 mL). The purple solution was stirred overnight, quenched with NaHCO ₃ , extracted with EtOAc, washed with brine, dried over Na ₂ SO ₄ and the solvent removed. The purple oil was purified by silica gel chromatography (0-100% EtOAc / hexanes gradient elution) to give the title compound as a white solid (9 mg, 0.017 mmol, 31.4% yield).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26-7.16 (m, 3H), 7.05 (m, 1H), 5.04 (s, 1H), 3.76-3.33 (m, 11H), 2.97-2.66 (m, 3H ), 2.42 (s, 3H), 2.23 (s, 3H), 1.84 (s, 3H), 1.74-1.45 (m, 7H), 0.95 (s, 9H). LCMS (ES +) (m / z): 521.69 (M + 1); 1064.21 (2M + 23).

Step 4: 2- (tert-Butoxy) -2- (5,8-dimethyl-2- (2-oxo-2- (piperidin-1-yl) ethyl) -6- (p-tolyl) -1,2 , 3,4-Tetrahydroisoquinolin-7-yl) acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.31 (m, 3H), 7.08 (m, 1H), 5.16 (m, 1H), 4.75 (m, 1H), 4.46 (m, 1H), 4.23 (m, 2H), 3.97-2.80 (m, 8H), 2.43 (s, 3H), 2.16 (s, 3H), 1.90 (s, 3H), 1.63 (m, 6H), 0.98 (s, 9H) .LCMS (ES + ) (m / z): 507.52 (M + 1).

[Example 8]
2- (tert-Butoxy) -2- (5,8-dimethyl-2-phenyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetic acid

Step 1: methyl 2- (tert-butoxy) -2- (5,8-dimethyl-2-phenyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetate

Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetate (25 mg, 0.063 mmol) in THF To the (2 ml) solution, Ruphos palladacycle (5.16 mg, 6.32 μmol) and iodobenzene (0.021 mL, 0.190 mmol) were added. The solution was stirred for 5 minutes under N ₂ atmosphere, then LHMDS (0.158 mL, 0.158 mmol) was added dropwise. A color change occurred and the solution was stirred for 30 minutes, cooled to 0 ° C., quenched with saturated NH ₄ Cl, extracted with EtOAc, dried over Na ₂ SO ₄ and the solvent removed. The resulting brown oil was subjected to the next step without further purification.
LCMS (ES +) (m / z): 472.51 (M + 1); 494.48 (M + 23).

Step 2: 2- (tert-butoxy) -2- (5,8-dimethyl-2-phenyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50-7.33 (m, 5H), 7.25 (m, 3H), 7.10 (m, 1H), 5.19 (m, 1H), 4.69 (m, 1H), 4.38 ( m, 1H), 3.87-3.62 (m, 2H), 3.12-2.83 (m, 2H), 2.42 (s, 3H), 2.22 (s, 3H), 1.91 (s, 3H), 0.99 (s, 9H) .LCMS (ES +) (m / z): 458.03 (M + 1); 915.79 (2M + 1).

[Example 9]
2- (tert-butoxy) -2- (5,8-dimethyl-2- (piperidine-1-carbonyl) -6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) Acetic acid

The title compound was made from piperidine-1-carbonyl chloride in a manner similar to that described in Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35 (m, 1H), 7.24 (m, 2H), 7.06 (m, 1H), 5.17 (m, 1H), 4.35 (m, 2H), 3.51 (m, 2H), 3.27 (m, 4H), 2.81 (m, 2H), 2.42 (s, 3H), 2.22 (s, 3H), 1.88 (s, 3H), 1.61 (m, 6H), 1.50-1.19 (m , 4H), 0.98 (s, 9H) .LCMS (ES +) (m / z): 493.53 (M + 1); 985.99 (2M + 1).

[Example 10]
2- (tert-Butoxy) -2- (2- (cyclohexylcarbamoyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetic acid

Step 1: methyl 2- (tert-butoxy) -2- (2- (cyclohexylcarbamoyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl )acetate

DCE of methyl 2- (tert-butoxy) -2- (5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetate (10 mg, 0.025 mmol) To the (1 mL) solution was added TEA (10.57 μl, 0.076 mmol) followed by isocyanatocyclohexane (6.46 μl, 0.051 mmol). The solution was stirred at room temperature for 30 min, quenched with 1M HCl, extracted with DCM, washed with brine, dried over Na ₂ SO ₄ and the solvent removed. The resulting purple oil was subjected to the next step without further purification. LCMS (ES +) (m / z): 543.47 (M + 23); 1041.99 (2M + 1).

Step 2: 2- (tert-butoxy) -2- (2- (cyclohexylcarbamoyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) Acetic acid

The title compound was made in a similar manner as described in Step 12 of Example 1 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.01 (m, 4H), 5.17 (s, 1H), 4.55 (m, 1H), 4.36 (m, 1H), 3.78-3.50 (m, 3H), 2.78 (m, 2H), 2.41 (s, 3H), 2.23 (s, 3H), 2.00 (m, 2H), 1.88 (s, 3H), 1.79-1.57 (m, 3H), 1.47-1.07 (m, 5H), 0.97 (s, 9H) .LCMS (ES +) (m / z): 507.46 (M + 1); 1014.02 (2M + 1).

[Example 11]
2- (tert-Butoxy) -2- (2-((3-fluorophenyl) sulfonyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-7- Yl) acetic acid

The title compound was made from 3-fluorobenzene-1-sulfonyl chloride in a manner similar to that described in Example 4 and isolated as a white solid after reverse phase HPLC.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (m, 1H), 7.57 (m, 2H), 7.38-7.18 (m, 4H), 7.04 (m, 1H), 5.14 (m, 1H), 4.43- 3.98 (m, 2H), 2.83 (m, 2H), 2.41 (s, 3H), 2.17 (s, 3H), 1.83 (s, 3H), 0.97 (s, 9H) .LCMS (ES +) (m / z ): 562.47 (M + 23); 1101.77 (2M + 23).

[Example 12]
(S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (piperidine-1-carbonyl) -6- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline- 7-yl) acetic acid

Step 1: (S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-2- (piperidine-1-carbonyl) -6- (p-tolyl) -1,2,3,4 -Tetrahydroisoquinolin-7-yl) acetate

The title compound was made from piperidine-1-carbonyl chloride in a manner similar to that described in Step 1 of Example 4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.22 (m, 3H), 7.05 (m, 1H), 5.05 (s, 1H), 4.35 (s, 2H), 3.67 (s, 3H), 3.62-3.40 ( m, 2H), 3.26 (m, 4H), 2.80 (m, 2H), 2.42 (s, 3H), 2.29 (s, 3H), 1.85 (s, 3H), 1.61 (m, 6H), 0.96 (s LCMS (ES +) (m / z): 507.53 (M + 1); 1013.98 (2M + 1).

Step 2: (S) -methyl 2- (tert-butoxy) -2- (5,8-dimethyl-2- (piperidine-1-carbonyl) -6- (p-tolyl) -1,2,3,4 -Tetrahydroisoquinolin-7-yl) acetate

  Using chiral chromatography, (S) -methyl 2- (tert-butoxy) -2- (5,8-dimethyl-2- (piperidine-1-carbonyl) -6- (p-tolyl) -1, 2,3,4-Tetrahydroisoquinolin-7-yl) acetate (40 mg, 0.079 mmol) was purified to give (S) -methyl 2- (tert-butoxy) -2- (5,8-dimethyl-2- ( Piperidine-1-carbonyl) -6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetate (8.5 mg, 0.017 mmol, 21.25% yield) was obtained as a white solid. Purification was performed under the following conditions: Whelk-O (S, S) column (250 × 30 mm ID, 5 μm; Regis Technologies, Morton Grove, Illinois) under high pressure conditions maintained at 23 ° C. The solution was fed with an Agilent HPLC 1100/1200 system (Agilent Technologies; Santa Clara, Calif.) Equipped with a DAD detector at a mixed flow rate of 45% EtOH and 55% hexane at 42.5 ml / min and monitored at 280 nm. The retention time of the title compound under these conditions was 6.77 minutes and the retention time of the undesired enantiomer was 7.75 minutes.

Chiral purity was determined by chiral analytical HPLC using a Whelk-O (S, S) column (250 × 4.6 mm ID, 5 μm; Regis Technologies, Morton Grove, Illinois) under high pressure conditions maintained at 23 ° C. . The solution was fed with an Agilent HPLC 1100/1200 system (Agilent Technologies; Santa Clara, CA) equipped with a DAD detector at a mixing flow rate of 50% EtOH and 50% hexane at 1 ml / min, and monitored at 280 nm. The retention time of the title compound under these conditions was 6.67 minutes and the retention time of the undesired enantiomer was 7.56 minutes. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.22 (m, 3H), 7.05 (m, 1H), 5.05 (s, 1H), 4.35 (s, 2H), 3.67 (s, 3H), 3.62-3.40 ( m, 2H), 3.26 (m, 4H), 2.80 (m, 2H), 2.42 (s, 3H), 2.29 (s, 3H), 1.85 (s, 3H), 1.61 (m, 6H), 0.96 (s LCMS (ES +) (m / z): 507.52 (M + 1); 1014.02 (2M + 1).

Step 3: (S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (piperidine-1-carbonyl) -6- (p-tolyl) -1,2,3,4- Tetrahydroisoquinolin-7-yl) acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36 (m, 1H), 7.24 (m, 2H), 7.06 (m, 1H), 5.18 (m, 1H), 4.35 (m, 2H), 3.49 (m, 2H), 3.26 (m, 4H), 2.80 (m, 2H), 2.41 (s, 3H), 2.21 (s, 3H), 1.88 (s, 3H), 1.61 (m, 6H), 0.98 (s, 9H LCMS (ES +) (m / z): 493.44 (M + 1); 985.89 (2M + 1).

[Example 13]
(S) -2- (tert-butoxy) -2- (2- (4,4-dimethylpiperidine-1-carbonyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) acetic acid

Step 1: (S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetate

Using chiral SFC chromatography, methyl 2- (tert-butoxy) -2- (5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) Acetate (650 mg, 1.643 mmol) was purified to give (S) -methyl 2- (tert-butoxy) -2- (5,8-dimethyl-6- (p-tolyl) -1,2,3,4- Tetrahydroisoquinolin-7-yl) acetate (229.1 mg, 0.579 mmol, 35.2% yield) was obtained as a white solid. Purification was performed under the following conditions: Chiral Tech IC column (250 × 20 mm ID, 5 μm; Chiral Tech, West Chester, PA) under supercritical conditions maintained at 40 ° C. and 100 bar. Methanol-modified CO ₂ (24.9% MeOH, 0.1% NH ₄ OH, 75% CO ₂ ) was fed with a PIC preparative SFC system (PIC Solution; Avignon, France) at a mixing flow rate of 45 ml / min. Selective collection was performed using Knauer's selectable 220 nm wavelength UV-visible light detector. The retention time of the title compound under these conditions was 12.84 minutes and the retention time of the undesired enantiomer was 10.45 minutes.

Chiral purity was determined by chiral analytical SFC on a Chiral Tech IC column (250 × 4.6 mm ID, 5 μm; Chiral Tech, West Chester, Pa.) Under supercritical conditions maintained at 40 ° C. and 140 bar. In the SFC system for analysis of PIC Solution (Avignon, France) equipped with a DAD detector, methanol-modified CO ₂ (24.9% MeOH, 0.1% NH ₄ OH, 75% CO ₂ ) was fed at a mixing flow rate of 2 ml / min. Monitored at 215 nm. The retention time of the title compound under these conditions was 9.38 minutes and the retention time of the undesired enantiomer was 8.16 minutes. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.22 (m, 3H), 7.06 (m, 1H), 5.04 (s, 1H), 3.96 (s, 2H), 3.66 (s, 3H), 3.15 (m, 2H), 2.66 (m, 2H), 2.42 (s, 3H), 2.23 (s, 3H), 1.84 (s, 3H), 0.95 (s, 9H) .LCMS (ES +) (m / z): 396.48 ( M + 1); 791.81 (2M + 1).

Step 2: (S) -2- (tert-butoxy) -2- (2- (4,4-dimethylpiperidine-1-carbonyl) -5,8-dimethyl-6- (p-tolyl) -1,2 , 3,4-Tetrahydroisoquinolin-7-yl) acetic acid

The title compound was made from 4,4-dimethylpiperidine-1-carbonyl chloride in a manner similar to that described in Step 1 of Example 4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.22 (m, 3H), 7.05 (m, 1H), 5.04 (s, 1H), 4.34 (s, 2H), 3.68 (s, 3H), 3.61-3.40 ( m, 2H), 3.28 (m, 4H), 2.80 (m, 2H), 2.42 (s, 3H), 2.29 (s, 3H), 1.85 (s, 3H), 1.40 (m, 4H), 0.97 (s LCMS (ES +) (m / z): 535.53 (M + 1); 557.53 (M + 23).

Step 3: (S) -2- (tert-butoxy) -2- (2- (4,4-dimethylpiperidine-1-carbonyl) -5,8-dimethyl-6- (p-tolyl) -1,2 , 3,4-Tetrahydroisoquinolin-7-yl) acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35 (m, 1H), 7.23 (m, 2H), 7.06 (m, 1H), 5.17 (s, 1H), 4.34 (m, 2H), 3.49 (m, 2H), 3.29 (m, 4H), 2.80 (m, 2H), 2.41 (s, 3H), 2.22 (s, 3H), 1.88 (s, 3H), 1.40 (m, 4H), 0.98 (s, 15H LCMS (ES +) (m / z): 521.50 (M + 1); 1042.09 (2M + 1).

[Example 14]
(S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (pyrrolidine-1-carbonyl) -6- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline- 7-yl) acetic acid

The title compound was made from pyrrolidine-1-carbonyl chloride in a manner similar to that described in Example 4 and isolated as a white solid after reverse phase HPLC.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36 (m, 1H), 7.24 (m, 2H), 7.06 (m, 1H), 5.17 (s, 1H), 4.40 (m, 2H), 3.55 (m, 2H), 3.46 (m, 4H), 2.81 (m, 2H), 2.42 (m, 3H), 2.22 (s, 3H), 1.88 (m, 7H), 0.98 (s, 9H) .LCMS (ES +) ( m / z): 501.63 (M + 23); 958.21 (2M + 1).

[Example 15]
(S) -2- (tert-butoxy) -2- (2-((4,4-dimethylpiperidin-1-yl) sulfonyl) -5,8-dimethyl-6- (p-tolyl) -1,2 , 3,4-Tetrahydroisoquinolin-7-yl) acetic acid

The title compound was made from 4,4-dimethylpiperidine-1-sulfonyl chloride in a manner similar to that described in Example 4, and was isolated as a TFA salt as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.72 (m, 1H), 7.35 (m, 1H), 7.23 (m, 2H), 7.06 (m, 1H), 5.17 (s, 1H), 4.33 (m, 2H), 3.50 (m, 2H), 3.27 (m, 4H), 2.82 (m, 2H), 2.41 (s, 3H), 2.19 (s, 3H), 1.88 (s, 3H), 1.43 (m, 4H ), 0.97 (m, 15H) .LCMS (ES +) (m / z): 557.45 (M + 1); 1135.97 (2M + 23).

[Example 16]
(S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (piperidin-1-ylsulfonyl) -6- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline -7-yl) acetic acid

The title compound was made from piperidine-1-sulfonyl chloride in a manner similar to that described in Example 4 and isolated as a white solid as a TFA salt after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.74 (m, 1H), 7.35 (m, 1H), 7.24 (m, 2H), 7.06 (m, 1H), 5.16 (s, 1H), 4.32 (m, 2H), 3.50 (m, 2H), 3.26 (m, 4H), 2.81 (m, 2H), 2.41 (s, 3H), 2.19 (s, 3H), 1.88 (s, 3H), 1.68-1.45 (m , 6H), 0.98 (s, 9H) .LCMS (ES +) (m / z): 529.53 (M + 1); 1057.98 (2M + 1).

[Example 17]
(S) -2- (tert-butoxy) -2- (2- (tert-butoxycarbonyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-7 -Il) Acetic acid

Step 1: (S) -tert-butyl 7- (1- (tert-butoxy) -2-methoxy-2-oxoethyl) -5,8-dimethyl-6- (p-tolyl) -3,4-dihydroisoquinoline -2 (1H) -carboxylate

(S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetate (10 mg, 0.025 To a solution of mmol) in MeOH (2 mL) was added TEA (10.57 μl, 0.076 mmol) followed by di-tert-butyl dicarbonate (11.04 mg, 0.051 mmol). The solution was stirred for 30 minutes, then diluted with EtOAc and 1M HCl, extracted with EtOAc, washed with brine, the solvent was removed, and the resulting purple oil was purified without further purification. We used for step of. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 (m, 1H), 7.05 (m, 1H), 5.04 (s, 1H), 4.51 (m, 2H), 3.72 (s, 2H), 3.68 (s, 3H), 2.74 (m, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 1.85 (s, 3H), 1.50 (m, 9H), 0.96 (s, 9H) .LCMS (ES +) ( m / z): 518.54 (M + 23); 992.00 (2M + 1).

Step 2: (S) -2- (tert-butoxy) -2- (2- (tert-butoxycarbonyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydro Isoquinolin-7-yl) acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36 (m, 1H), 7.23 (m, 2H), 7.07 (m, 1H), 5.17 (m, 1H), 4.51 (m, 2H), 3.69 (m, 2H), 2.74 (m, 2H), 2.42 (s, 3H), 2.21 (s, 3H), 1.88 (s, 3H), 1.51 (s, 9H), 0.99 (s, 9H). LCMS (ES +) ( m / z): 504.43 (M + 23).

[Example 18]
(S) -2- (tert-butoxy) -2- (2-((cyclohexylmethyl) sulfonyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline- 7-yl) acetic acid

The title compound was made from cyclohexylmethanesulfonyl chloride in a manner similar to that described in Example 4 and isolated as a TFA salt as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.72 (m, 1H), 7.35 (m, 1H), 7.24 (m, 2H), 7.06 (m, 1H), 5.17 (s, 1H), 4.57-4.17 ( m, 2H), 3.78-3.34 (m, 2H), 2.86 (m, 4H), 2.42 (s, 3H), 2.20 (s, 3H), 2.02 (m, 3H), 1.89 (s, 3H), 1.72 (m, 3H), 1.40-1.05 (m, 5H), 0.98 (s, 9H) .LCMS (ES +) (m / z): 564.42 (M + 23); 1106.74 (2M + 23).

[Example 19]
(S) -2- (tert-Butoxy) -2- (2- (cyclohexylsulfonyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl Acetic acid

The title compound was made from cyclohexanesulfonyl chloride in a manner similar to that described in Example 4, and was isolated as a TFA salt as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.73 (m, 1H), 7.35 (m, 1H), 7.24 (m, 2H), 7.07 (m, 1H), 5.17 (s, 1H), 4.57-4.29 ( m, 2H), 3.78-3.49 (m, 2H), 3.77-3.47 (m, 2H), 3.09-2.71 (m, 3H), 2.42 (s, 3H), 2.25 2.09 (m, 5H), 1.96-1.84 (m, 5H), 1.66-1.47 (m, 6H), 0.98 (s, 9H) .LCMS (ES +) (m / z): 550.41 (M + 23); 1077.97 (2M + 23).

[Example 20]
(S) -2- (tert-butoxy) -2- (2- (3,3-dimethylbutanoyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydro Isoquinolin-7-yl) acetic acid

The title compound was made from 3,3-dimethylbutanoyl chloride in a manner similar to that described in Example 4 and isolated as a white solid after reverse phase HPLC.
¹ H NMR (400 MHz, CDCl ₃ ) δ (mixture of rotamers) 7.36 (m, 1H), 7.24 (m, 2H), 7.07 (m, 1H), 5.17 (m, 1H), 4.98-4.44 ( m, 2H), 4.01-3.59 (m, 2H), 2.78 (m, 2H), 2.49-2.14 (m, 8H), 1.88 (s, 3H), 1.16-0.92 (m, 18H) .LCMS (ES +) (m / z): 480.60 (M + 1); 960.14 (2M + 1).

[Example 21]
2- (tert-Butoxy) -2- (2-cyclohexyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: benzyl 6-hydroxy-5,8-dimethyl-7- (p-tolyl) -3,4-dihydroisoquinoline-2 (1H) -carboxylate

A solution of benzyl 7-bromo-6-hydroxy-5,8-dimethyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate (270 mg, 0.692 mmol) in DMF (100 mL) is degassed for 5 minutes, p- Tolylboronic acid (235 mg, 1.730 mmol), Pd (Ph ₃ P) ₄ (160 mg, 0.138 mmol) and Na ₂ CO ₃ (0.899 mL, 1.799 mmol) were added and the solution was heated to 80 ° C. and stirred for 1.5 hours. . The solution was cooled to room temperature, diluted with di-ethyl ether and water, extracted with di-ethyl ether, dried over Na ₂ SO ₄ and the solvent removed. The resulting oil was purified by silica gel chromatography (gradient elution with 0-20% EtOAc / hexanes) to give the title compound as a yellow oil (21 g, 52.3 mmol, 91% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.28 (m, 7H), 7.14 (m, 2H), 5.21 (s, 2H), 4.73 (s, 1H), 4.54 (s, 2H), 3.77 ( m, 2H), 2.81 (m, 2H), 2.44 (s, 3H), 2.17 (s, 3H), 1.92 (s, 3H) .LCMS (ES +) (m / z): 402.43 (M + 1); 803.79 (2M + 1).

Step 2: benzyl 5,8-dimethyl-7- (p-tolyl) -6-(((trifluoromethyl) sulfonyl) oxy) -3,4-dihydroisoquinoline-2 (1H) -carboxylate

To a solution of benzyl 6-hydroxy-5,8-dimethyl-7- (p-tolyl) -3,4-dihydroisoquinoline-2 (1H) -carboxylate (2.94 g, 7.32 mmol) was added K ₂ CO ₃ (2.226 g 16.11 mmol) and PhNTf ₂ (5.76 g, 16.11 mmol) were added. The suspension was stirred at room temperature for 2 hours, diluted with diethyl ether and water, extracted with diethyl ether, dried over Na ₂ SO ₄ and the solvent removed. The resulting yellow oil was purified by silica gel chromatography (0-15% EtOAc / hexanes gradient elution) to give the title compound as a white foam (3.49 g, 6.54 mmol, 89% yield). .
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.29 (m, 5H), 7.24 (m, 2H), 7.08 (m, 2H), 5.21 (s, 2H), 4.58 (s, 2H), 3.79 ( m, 2H), 2.82 (m, 2H), 2.41 (s, 3H), 2.29 (s, 3H), 1.98 (s, 3H) .LCMS (ES +) (m / z): 534.43 (M + 1); 1067.83 (2M + 1).

Step 3: benzyl 5,8-dimethyl-7- (p-tolyl) -6-vinyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate

Benzyl 5,8-dimethyl-7- (p-tolyl) -6-(((trifluoromethyl) sulfonyl) oxy) -3,4-dihydroisoquinoline-2 (1H) -carboxylate (3.49 g, 6.54 mmol) Of 1-propanol (100 mL) was degassed with N ₂ for 10 min. Vinyl trifluoroborate (3.50 g, 26.2 mmol), TEA (6.38 mL, 45.8 mmol), PdCl ₂ (dppf) -CH ₂ Cl ₂ adduct (0.604 g, 0.739 mmol) were added and the suspension was added for 2 hours. Heat to 135 ° C., dilute with EtOAc and water, pour onto ice water, extract with EtOAc, dry over Na ₂ SO ₄ and remove the solvent. The resulting red oil was purified by silica gel chromatography (0-20% EtOAc / hexanes gradient elution) to give the title compound as a yellow oil (2.48 g, 6.03 mmol, 92% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47-7.29 (m, 5H), 7.18 (m, 2H), 6.96 (m, 2H), 6.34 (m, 1H), 5.29-5.14 (m, 3H), 4.95 (m, 1H), 4.60 (s, 2H), 3.79 (m, 2H), 2.84 (m, 2H), 2.40 (s, 3H), 2.28 (s, 3H), 1.91 (s, 3H) .LCMS (ES +) (m / z): 412.45 (M + 1); 823.73 (2M + 1).

Step 4: benzyl 6-formyl-5,8-dimethyl-7- (p-tolyl) -3,4-dihydroisoquinoline-2 (1H) -carboxylate

Benzyl 5,8-dimethyl-7- (p-tolyl) -6-vinyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate (2.68 g, 6.51 mmol) in THF / H ₂ O (3: 1 13 mL) solution was added potassium osmate dihydrate (0.720 g, 1.954 mmol) followed by sodium periodate (8.36 g, 39.1 mmol). The solution was stirred for 1 hour, diluted with EtOAc and sodium thiosulfate, extracted with EtOAc, dried over Na ₂ SO ₄ and the solvent removed. The resulting brown oil was purified by silica gel chromatography (gradient elution with 0-100% EtOAc / hexanes) to give the title compound as a white solid (1.446 g, 3.50 mmol, 53.7% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.73 (s, 1H), 7.46-7.29 (m, 5H), 7.24 (m, 2H), 7.04 (m, 2H), 5.21 (s, 2H), 4.63 ( s, 2H), 3.79 (m, 2H), 2.86 (m, 2H), 2.48 (s, 3H), 2.42 (s, 3H), 1.96 (s, 3H) .LCMS (ES +) (m / z): 414.41 (M + 1); 827.67 (2M + 1).

Step 5: benzyl 6- (cyano ((trimethylsilyl) oxy) methyl) -5,8-dimethyl-7- (p-tolyl) -3,4-dihydroisoquinoline-2 (1H) -carboxylate

To a solution of benzyl 6-formyl-5,8-dimethyl-7- (p-tolyl) -3,4-dihydroisoquinoline-2 (1H) -carboxylate (1.446 g, 3.50 mmol) in DCM (50 mL) at 0 ° C. Zinc iodide (0.558 g, 1.748 mmol) was added followed by TMS-CN (6.56 mL, 49.0 mmol). The solution was stirred for 1 hour, diluted with DCM, poured onto ice, extracted with DCM, dried over Na ₂ SO ₄ and the solvent removed. The resulting cloudy yellow oil was subjected to the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.31 (m, 5H), 7.26 (m, 2H), 7.01 (m, 2H), 5.36 (s, 1H), 5.21 (s, 2H), 4.56 ( s, 2H), 3.88-3.64 (m, 2H), 2.84 (m, 2H), 2.52 (s, 3H), 2.44 (s, 3H), 1.87 (s, 3H), 0.00 (s, 9H) .LCMS (ES +) (m / z): 535.44 (M + 23).

Step 6: methyl 2- (5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2-hydroxyacetate

HCl gas was bubbled into MeOH for 20 minutes at 0 ° C. to make a saturated HCl solution. The solution (150 mL) was added at 0 ° C. to benzyl 6- (cyano ((trimethylsilyl) oxy) methyl) -5,8-dimethyl-7- (p-tolyl) -3,4-dihydroisoquinoline-2 (1H) -carboxyl. To a flask containing the rate (1.519 g, 2.96 mmol). Stir the solution at 0 ° C. for 5 minutes, warm to room temperature, stir for 2 hours, cool and return to 0 ° C., blow HCl into the solution for 1 hour, stir at 0 ° C. for 1 hour, warm to room temperature And stirred for 1 hour. MeOH was removed by rotary evaporation without being immersed in a water bath. The resulting turbid oil was suspended in 1M HCl (100 mL), heated to 90 ° C. for 2.5 hours, poured onto ice / water, neutralized with 50% NaOH and 1M NaOH, 1: 3 IPA Extraction with / CHCl ₃ and removal of the solvent provided the colorless oil without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-6.98 (m, 4H), 5.09 (s, 1H), 4.70 (s, 1H), 3.96 (s, 2H), 3.70 (s, 3H), 3.18 ( m, 2H), 2.72 (m, 2H), 2.41 (s, 3H), 2.16 (s, 3H), 1.81 (s, 3H) .LCMS (ES +) (m / z): 340.39 (M + 1), 679.65 (2M + 1).

Step 7: methyl 2- (tert-butoxy) -2- (5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Methyl 2- (5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2-hydroxyacetate (1 g, 2.95 mmol) tert-butyl acetate ( To a solution (200 mL, 1481 mmol) was added perchloric acid (0.886 mL, 14.73 mmol). The solution is stirred for 30 minutes, then diluted with EtOAc and water, cooled to 0 ° C., made basic (pH 10) with 1M NaOH and 50% NaOH, extracted with EtOAc and dried over Na ₂ SO _4. The solvent was removed. The resulting tan solid was purified by silica gel chromatography (gradient elution 0-10% MeOH / DCM) to give the title compound as a white solid (618 mg, 1.562 mmol, 53.0% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 (m, 3H), 7.05 (m, 1H), 5.03 (s, 1H), 4.00 (s, 2H), 3.67 (s, 3H), 3.24 (m, 2H), 2.74 (m, 2H), 2.43 (s, 3H), 2.28 (s, 3H), 1.791 (s, 3H), 0.95 (s, 9H) .LCMS (ES +) (m / z): 396.50 ( M + 1), 791.95 (2M + 1).

Step 8: methyl 2- (tert-butoxy) -2- (2-cyclohexyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

The title compound was made from cyclohexanone in a manner similar to that described in Step 11 of Example 1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20 (m, 3H), 7.05 (m, 1H), 5.00 (s, 1H), 3.76-3.57 (m, 5H), 2.93-2.72 (m, 4H), 2.58-2.31 (m, 5H), 2.25 (s, 3H), 2.03-1.52 (m, 12H), 0.94 (s, 9H) .LCMS (ES +) (m / z): 478.58 (M + 1); 500.56 (M + 23).

Step 9: 2- (tert-Butoxy) -2- (2-cyclohexyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made in a similar manner as described in Step 12 of Example 1 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32 (m, 1H), 7.25 (m, 2H), 7.10 (m, 1H), 5.17 (m, 1H), 4.49 (m, 1H), 4.02 (m, 1H), 3.76 (m, 1H), 3.45-3.11 (m, 3H), 2.96 (m, 1H), 2.42 (s, 3H), 2.23 (m, 5H), 1.99 (m, 2H), 1.87 (s , 3H), 1.81-1.32 (m, 6H), 0.94 (s, 9H) .LCMS (ES +) (m / z): 464.31 (M + 1); 927.93 (2M + 1).

[Example 22]
2- (tert-Butoxy) -2- (2- (3-fluorobenzoyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from 3-fluorobenzoic acid in a manner similar to that described in Example 5 and isolated as a residue after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ (mixture of rotamers) 7.61-6.62 (m, 8H), 5.34-5.04 (m, 1H), 5.02-4.81 (m, 1H), 4.74-3.20 (m , 4H), 3.05-2.57 (m, 2H), 2.45-1.79 (m, 9H), 0.97 (s, 9H). LCMS (ES +) (m / z): 526.31 (M + 23).

[Example 23]
2- (tert-Butoxy) -2- (5,8-dimethyl-2- (piperidine-1-carbonyl) -7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) Acetic acid

The title compound was made from piperidine-1-carbonyl chloride in a manner similar to that described in Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35 (m, 1H), 7.23 (m, 2H), 7.07 (m, 1H), 5.17 (m, 1H), 4.31 (m, 2H), 3.50 (m, 2H), 3.27 (m, 3H), 2.82 (m, 2H), 2.41 (s, 3H), 2.23 (s, 3H), 1.87 (s, 3H), 1.60 (m, 6H), 0.98 (s, 9H LCMS (ES +) (m / z): 493.52 (M + 1); 985.94 (2M + 1).

[Example 24]
(S) -2- (tert-Butoxy) -2- (5,8-dimethyl-2-pivaloyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: (S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Using chiral SFC chromatography, methyl 2- (tert-butoxy) -2- (5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) Acetate (550 mg, 1.391 mmol) was purified to (S) -methyl 2- (tert-butoxy) -2- (5,8-dimethyl-7- (p-tolyl) -1,2,3,4- Tetrahydroisoquinolin-6-yl) acetate (200.1 mg, 0.506 mmol, 36.4% yield) was obtained as a white solid. Purification was performed under the following conditions: Chiral Tech CC ₄ column (250 × 30 mm ID, 10 μm; Chiral Tech, West Chester, PA) under supercritical conditions maintained at 40 ° C. and 140 bar. Methanol-modified CO ₂ (19.9% MeOH, 0.1% NH ₄ OH, 80% CO ₂ ) was fed with a PIC preparative SFC system (PIC Solution; Avignon, France) at a mixing flow rate of 90 ml / min. Selective recovery was performed using a Knauer selectable, 220 nm wavelength UV-visible light detector. The retention time of the title compound under these conditions was 11.58 minutes and the retention time of the undesired enantiomer was 9.17 minutes.

Chiral purity was determined by chiral analytical SFC on a Chiral Tech CC ₄ column (250 x 4.6 mm ID, 5 μm; Chiral Tech, West Chester, PA) under supercritical conditions maintained at 40 ° C and 140 bar. . With a SFC system for analysis of PIC Solution equipped with a DAD detector (Avignon, France), methanol-modified CO ₂ (19.9% MeOH, 0.1% NH ₄ OH, 80% CO ₂ ) was fed at a mixing flow rate of 2 ml / min. Monitored at 220 nm. The retention time of the title compound under these conditions was 8.12 minutes and the retention time of the undesired enantiomer was 6.88 minutes. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.22 (m, 3H), 7.06 (m, 1H), 5.03 (s, 1H), 4.04-3.56 (m, 5H), 3.40-3.60 (m, 5H), 2.42 (s, 3H), 2.28 (s, 3H), 1.80 (s, 3H), 0.95 (s, 9H).
LCMS (ES +) (m / z): 396.39 (M + 1); 791.88 (2M + 1).

Step 2: (S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-2-pivaloyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6- Yl) acetate

The title compound was made from pivaloyl chloride in a manner similar to that described in Step 1 of Example 4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 (m, 3H), 7.04 (m, 1H), 5.03 (s, 1H), 4.66 (m, 2H), 4.03-3.76 (m, 2H), 3.67 ( s, 3H), 2.80 (m, 2H), 2.42 (s, 3H), 2.29 (s, 3H), 1.86 (s, 3H), 1.34 (s, 9H), 0.95 (s, 9H) .LCMS (ES + ) (m / z): 480.47 (M + 1); 502.47 (M + 23).

Step 3: (S) -2- (tert-butoxy) -2- (5,8-dimethyl-2-pivaloyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl Acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35 (m, 1H), 7.24 (m, 2H), 7.06 (m, 1H), 5.17 (s, 1H), 4.91-4.41 (m, 2H), 4.08- 3.68 (m, 2H), 2.82 (m, 2H), 2.42 (s, 3H), 2.23 (s, 3H), 1.89 (s, 3H), 1.35 (s, 9H), 0.97 (s, 9H) .LCMS (ES +) (m / z): 466.65 (M + 1); 488.61 (M + 23).

[Example 25]
(S) -2- (tert-butoxy) -2- (2- (3,3-dimethylbutanoyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydro Isoquinolin-6-yl) acetic acid

The title compound was made from 3,3-dimethylbutanoyl chloride in a manner similar to that described in Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ (mixture of rotamers) 7.35 (m, 1H), 7.23 (m, 2H), 7.07 (m, 1H), 5.18 (m, 1H), 4.98-4.38 ( m, 2H), 4.03-3.60 (m, 2H), 2.80 (m, 2H), 2.48-2.29 (m, 5H), 2.23 (m, 3H), 1.90 (m, 3H), 1.17-0.90 (m, 18H) .LCMS (ES +) (m / z): 480.58 (M + 1); 960.12 (2M + 1).

[Example 26]
(S) -2- (tert-butoxy) -2- (2- (3-fluoro-2-methoxybenzoyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4- Tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from 3-fluoro-2-methoxybenzoic acid in a manner similar to that described in Example 5, and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ (mixture of rotamers) 7.42-6.95 (m, 7H), 5.18 (m, 1H), 5.05-4.61 (m, 1H), 4.44-3.80 (m, 4H ), 3.53 (m, 2H), 2.96-2.62 (m, 2H), 2.41 (m, 3H), 2.24 (m, 3H), 1.96 (m, 3H), 0.99 (m, 9H) .LCMS (ES +) (m / z): 534.59 (M + 1); 1068.03 (2M + 1).

[Example 27]
(S) -2- (tert-butoxy) -2- (2- (tert-butoxycarbonyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6 -Il) Acetic acid

The title compound was made from di-tert-butyl dicarbonate in a manner similar to that described in Example 17, and was isolated as a TFA salt as a white solid after reverse phase HPLC.
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.77 (m, 1H), 7.35 (m, 1H), 7.23 (m, 2H), 7.06 (m, 1H), 5.18 (m, 1H), 4.53 (m, 2H), 3.67 (m, 2H), 2.76 (m, 2H), 2.41 (s, 3H), 2.23 (s, 3H), 1.87 (s, 3H), 1.50 (s, 9H), 0.98 (s, 9H LCMS (ES +) (m / z): 504.41 (M + 23).

[Example 28]
(S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (tetrahydro-2H-pyran-4-yl) -7- (p-tolyl) -1,2,3,4 -Tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from dihydro-2H-pyran-4 (3H) -one in a manner similar to that described in Example 1 and isolated as a TFA salt as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.79 (m, 1H), 7.39-7.21 (m, 3H), 7.09 (m, 1H), 5.17 (s, 1H), 4.52 (m, 1H), 4.24- 3.94 (m, 1H), 3.88-3.57 (m, 2H), 3.49 (m, 2H), 3.22 (m, 2H), 2.99 (m, 1H), 2.42 (s, 3H), 2.24 (s, 3H) , 2.05 (m, 4H), 1.87 (s, 3H), 0.96 (s, 9H) .LCMS (ES +) (m / z): 466.54 (M + 1); 932.00 (2M + 1).

[Example 29]
(S) -2- (tert-Butoxy) -2- (2-cyclohexyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from cyclohexanone in a manner similar to that described in Example 1 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32 (m, 1H), 7.26 (m, 2H), 7.10 (m, 1H), 5.16 (m, 1H), 4.48 (m, 1H), 4.09-2.88 ( m, 5H), 2.43 (s, 3H), 2.23 (m, 5H), 1.98 (m, 2H), 1.87 (s, 3H), 1.81-1.18 (m, 7H), 0.95 (s, 9H).
LCMS (ES +) (m / z): 464.52 (M + 1).

[Example 30]
(S) -2- (tert-butoxy) -2- (2- (3-fluorobenzyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6 -Il) Acetic acid

The title compound was made from 3-fluorobenzaldehyde in a manner similar to that described in Example 1 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (m, 1H), 7.36-7.15 (m, 6H), 7.06 (m, 1H), 5.17 (m, 1H), 4.63-2.92 (m, 6H), 2.42 (s, 3H), 2.24 (s, 3H), 1.79 (s, 3H), 0.96 (s, 9H) .LCMS (ES +) (m / z): 490.41 (M + 1); 512.41 (M + 23 ).

[Example 31]
(S) -2- (tert-butoxy) -2- (2- (cyclohexylmethyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl Acetic acid

The title compound was made from cyclohexanecarbaldehyde in a manner similar to that described in Example 1 and isolated as a white solid after reverse phase HPLC as a TFA salt. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (m, 1H), 7.35 (m, 1H), 7.21 (m, 2H), 7.03 (m, 1H), 5.11 (s, 1H), 3.95-3.58 ( m, 2H), 3.05 (m, 2H), 2.87 (m, 2H), 2.75-2.52 (m, 2H), 2.41 (s, 3H), 2.25 (s, 3H), 1.98-1.63 (m, 10H) , 1.39-0.80 (m, 13H) .LCMS (ES +) (m / z): 478.48 (M + 1).

[Example 32]
(S) -2- (tert-Butoxy) -2- (2-cyclopentyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was prepared from cyclopentanone in a manner similar to that described in Example 1 and isolated as a white solid as a TFA salt after reverse phase HPLC.
¹ H NMR (400 MHz, CDCl ₃ ) δ 12.29 (m, 1H), 7.36-7.23 (m, 3H), 7.09 (m, 1H), 5.17 (s, 1H), 4.63 (m, 1H), 4.03- 3.76 (m, 2H), 3.57 (m, 1H), 3.23 (m, 1H), 2.96 (m, 1H), 2.42 (s, 3H), 2.23 (s, 3H), 2.11 (m, 4H), 1.99 -1.79 (m, 5H), 1.68 (m, 2H), 0.96 (s, 9H) .LCMS (ES +) (m / z): 450.56 (M + 1).

[Example 33]
(S) -2- (tert-Butoxy) -2- (5,8-dimethyl-2-neopentyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from pivalaldehyde in a manner similar to that described in Example 1 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36 (m, 1H), 7.22 (m, 2H), 7.07 (m, 1H), 5.17 (s, 1H), 3.60 (m, 2H), 2.95-2.06 ( m, 12H), 1.80 (m, 3H), 1.07-0.82 (m, 18H) .LCMS (ES +) (m / z): 452.47 (M + 1); 474.48 (2M + 1).

[Example 34]
(S) -2- (tert-Butoxy) -2- (5,8-dimethyl-2-phenethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from 2-phenylacetaldehyde in a manner similar to that described in Example 1, and was isolated as a TFA salt as a white solid after reverse phase HPLC.
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.21 (s, 1H), 7.41-7.18 (m, 7H), 7.05 (m, 1H), 5.16 (s, 1H), 4.14-3.89 (m, 2H), 337-2.81 (m, 8H), 2.42 (s, 3H), 2.24 (s, 3H), 1.80 (s, 3H), 0.97 (s, 9H) .LCMS (ES +) (m / z): 486.45 (M +1); 508.47 (M + 23).

[Example 35]
(S) -2- (tert-Butoxy) -2- (2- (cyclohexylcarbamoyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl Acetic acid

The title compound was made from isocyanatocyclohexane in a manner similar to that described in Example 10 and isolated as a TFA salt as a white solid after reverse phase HPLC.
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.67 (m, 1H), 7.36 (m, 1H), 7.24 (m, 2H), 7.06 (m, 1H), 5.17 (m, 1H), 4.61-4.23 ( m, 2H), 3.78-3.53 (m, 3H), 3.99-3.59 (m, 1H), 3.31 (m, 2H), 2.81 (m, 2H), 2.42 (s, 3H), 2.24 (s, 3H) , 2.09-1.94 (m, 4H), 1.90 (s, 3H), 1.79-1.58 (m, 3H), 1.47-1.22 (m, 3H), 0.98 (s, 9H) .LCMS (ES +) (m / z ): 507.66 (M + 1); 1014.27 (2M + 1).

[Example 36]
(S) -2- (tert-Butoxy) -2- (5,8-dimethyl-2-phenyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from iodobenzene in a manner similar to that described in Example 8 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50-7.33 (m, 5H), 7.27 (m, 3H), 7.10 (s, 1H), 5.20 (m, 1H), 4.78-4.24 (m, 2H), 3.92-3.55 (m, 2H), 3.21-2.86 (m, 2H), 2.42 (s, 3H), 2.26 (s, 3H), 1.89 (s, 3H), 0.98 (s, 9H) .LCMS (ES +) (m / z): 458.42 (M + 1); 480.37 (M + 23).

[Example 37]
(S) -2- (tert-butoxy) -2- (2- (2-cyclohexylacetyl) -5,8-dimethyl-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-7 -Il) Acetic acid

The title compound was made from 2-cyclohexylacetyl chloride in a manner similar to that described in Example 4 and isolated as a white solid after reverse phase HPLC.
¹ H NMR (CDCl3) δ: 7.35 (m, 1H), 7.24 (m, 2H), 7.07 (m, 1H), 5.17 (m, 1H), 4.97-4.41 (m, 2H), 3.99-3.57 (m , 2H), 2.77 (m, 2H), 2.47-2.15 (m, 8H), 1.97-1.55 (m, 2H), 1.46-0.78 (m, 14H). LCMS ES + (m / z): 506.60 (M + 1), 1012.15 (2M + 1).

[Example 38]
(S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (piperidin-1-ylsulfonyl) -7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline -6-yl) acetic acid

The title compound was made from piperidine-1-sulfonyl chloride in a manner similar to that described in Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (CDCl3) ∂: 7.35 (m, 1H), 7.24 (m, 2H), 7.07 (m, 1H), 5.18 (s, 1H), 4.29 (m, 2H), 3.52 (m, 2H), 3.25 (m, 4H), 2.85 (m, 2H), 2.42 (m, 3H), 2.23 (m, 3H), 1.85 (m, 3H), 1.68-1.52 (m, 6H), 0.98 (m, 9H) LCMS ES + (m / z): 529.59 (M + 1), 1058.08 (2M + 1).

[Example 39]
(S) -2- (tert-butoxy) -2- (2- (2-cyclohexylethyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6 -Il) Acetic acid

The title compound was made from 2-cyclohexylacetaldehyde in a manner similar to that described in Example 1 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (CDCl3) 7.: 7.36-7.22 (m, 3H), 7.08 (m, 1H), 5.17 (m, 1H), 4.59 (m, 1H), 3.83 (m, 2H), 3.19 (m, 4H ), 2.95 (m, 1H), 2.42 (m, 3H), 2.24 (m, 3H), 1.85 (m, 3H), 1.72 (m, 7H), 1.43-1.10 (m, 6H), 0.96 (m, 9H) .LCMS ES + (m / z): 492.63 (M + 1), 984.19 (2M + 1).

[Example 40]
(S) -2- (tert-Butoxy) -2- (2- (4,4-dimethylcyclohexyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline -6-yl) acetic acid

The title compound was made from 4,4-dimethylcyclohexanone in a manner similar to that described in Example 1 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (CDCl3) ∂: 7.36-7.22 (m, 3H), 7.09 (m, 1H), 5.16 (m, 1H), 4.49 (m, 1H), 4.01 (m, 1H), 3.76 (m, 1H ), 3.24 (m, 3H), 2.94 (m, 1H), 2.41 (m, 3H), 2.23 (m, 3H), 2.02 (m, 2H), 1.86 (m, 5H), 1.59 (m, 4H) , 0.96 (m, 15H). LCMS ES + (m / z): 492.64 (M + 1).

[Example 41]
(S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (phenylsulfonyl) -7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl Acetic acid

The title compound was made from benzenesulfonyl chloride in a manner similar to that described in Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (CDCl3) ∂: 7.87 (m, 2H), 7.66-7.51 (m, 3H), 7.37-7.18 (m, 3H), 7.04 (m, 1H), 5.14 (m, 1H), 4.33 (m , 1H), 3.95 (m, 1H), 3.62 (m, 1H), 3.13 (m, 1H), 2.86 (m, 2H), 2.41 (m, 3H), 2.18 (m, 3H), 1.82 (m, 3H), 0.95 (m, 9H) .LCMS ES + (m / z): 522.38 (M + 1), 1065.90 (2M + 23).

[Example 42]
(S) -2- (tert-Butoxy) -2- (5,8-dimethyl-2-picolinoyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from picolinic acid in a manner similar to that described in Example 5 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (CDCl3) ∂: 8.69 (m, 1H), 7.89 (m, 1H), 7.73 (m, 1H), 7.52-6.95 (m, 5H), 5.26-4.50 (m, 3H), 4.14-3.54 (m, 2H), 3.02-2.70 (m, 2H), 2.41 (m, 3H), 2.24 (m, 3H), 2.01-1.62 (m, 3H), 0.98 (m, 9H). LCMS ES + (m / z): 487.44 (M + 1), 973.98 (2M + 1).

[Example 43]
(S) -2- (tert-Butoxy) -2- (5,8-dimethyl-2-nicotinoyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from nicotinic acid in a manner similar to that described in Example 5 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (CDCl3) ∂: 8.86 (m, 1H), 8.17 (m, 1H), 7.71 (m, 1H), 7.46-7.17 (m, 4H), 7.08 (m, 1H), 5.19 (m, 1H ), 5.07-4.44 (m, 2H), 4.18-3.54 (m, 2H), 2.88 (m, 2H), 2.42 (m, 3H), 2.25 (m, 3H), 2.03-1.59 (m, 3H), 0.99 (m, 9H). LCMS ES + (m / z): 487.53 (M + 1).

[Example 44]
(S) -2- (tert-Butoxy) -2- (2-isonicotinoyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from isonicotinic acid in a manner similar to that described in Example 5 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (CDCl3) ∂: 8.87 (m, 2H), 7.67 (m, 2H), 7.38-7.25 (m, 3H), 7.04 (m, 1H), 5.18 (m, 1H), 4.99-4.65 (m , 2H), 4.11-3.50 (m, 2H), 2.97-2.76 (m, 2H), 2.41 (m, 3H), 2.24 (m, 3H), 1.98-1.59 (m, 3H), 0.98 (m, 9H LCMS ES + (m / z): 487.54 (M + 1).

[Example 45]
(S) -2- (tert-butoxy) -2- (2- (cyclohexylsulfonyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl Acetic acid

The title compound was made from cyclohexanesulfonyl chloride in a manner similar to that described in Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (CDCl3) 7 .: 7.35 (m, 1H), 7.24 (m, 2H), 7.07 (m, 1H), 5.18 (m, 1H), 4.57-4.21 (m, 2H), 3.81-3.40 (m , 3H), 3.08-2.74 (m, 3H), 2.42 (m, 3H), 2.27-2.07 (m, 5H), 1.96-1.79 (m, 5H), 1.66-1.44 (m, 5H), 0.98 (m LCMS ES + (m / z): 528.26 (M + 1), 550.11 (M + 23), 1077.88 (2M + 23).

[Example 46]
(S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (2-oxo-2- (piperidin-1-yl) acetyl) -7- (p-tolyl) -1, 2,3,4-Tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from 2-oxo-2- (piperidin-1-yl) acetic acid in a manner similar to that described in Example 5 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) (mixture of rotamers) δ ppm 7.37-7.20 (m, 3H), 7.13-7.00 (m, 1H), 5.11-5.02 (m, 1H), 4.76-4.43 (m, 2H), 4.00-3.50 (m, 4H), 3.47-3.21 (m, 2H), 2.88 (t, J = 5.4 Hz, 2H), 2.42 (s, 3H), 2.29 (br. s., 3H), 1.96 - 1.79 (m , 3H), 1.78 - 1.50 (m, 5H), 1.44 - 1.26 (m, 1H), 0.92 (s, 9H); LCMS (m / z) ES - = 519.1 (M- 1).

[Example 47]
(S) -2- (tert-Butoxy) -2- (2- (cyclohexanecarbonyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl Acetic acid

The title compound was made from cyclohexanecarboxylic acid in a manner similar to that described in Example 5 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) (mixture of rotamers) δ ppm 7.39-7.18 (m, 3H), 7.15-6.99 (m, 1H), 5.06 (s, 1H), 4.75-4.51 (m , 2H), 3.95-3.75 (m, 2H), 2.94-2.69 (m, 3H), 2.42 (s, 3H), 2.36-2.21 (m, 3H), 1.96-1.65 (m, 8H), 1.60-1.19 (m, 5H), 0.92 ( s, 9H); LCMS (m / z) ES + = 492.1 (M + 1), ES - = 490.1 (M-1).

[Example 48]
(S) -2- (2-Benzoyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2- (tert-butoxy) acetic acid

The title compound was made from benzoic acid in a manner similar to that described in Example 5 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) (mixture of rotamers) δ ppm 7.62-7.39 (m, 5H), 7.36-7.17 (m, 3H), 7.15-6.93 (m, 1H), 5.14-4.99 (m, 1H), 4.83-4.46 (m, 2H), 4.10-3.62 (m, 2H), 2.99-2.73 (m, 2H), 2.52-2.36 (m, 3H), 2.30 (br. s., 3H ), 2.02 - 1.50 (m, 3H), 0.93 (s, 9H); LCMS (m / z) ES + = 486.1 (M + 1), ES - = 484.1 (M-1).

[Example 49]
(2S) -2- (2- (Bicyclo [2.2.1] heptan-2-yl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6- Yl) -2- (tert-butoxy) acetic acid

The title compound was made from norcamphor in a manner similar to that described in Step 11 of Example 1 and hydrolyzed in a manner similar to that described in Step 2 of Example 4. The product was isolated as a white solid after reverse phase HPLC as a TFA salt. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.36-7.19 (m, 3H), 7.14-6.98 (m, 1H), 5.07 (s, 1H), 4.56-4.18 (m, 2H), 3.93-3.80 (m, 1H), 3.77-3.57 (m, 1H), 3.48-3.26 (m, 1H), 3.18-3.04 (m, 2H), 2.88-2.75 (m, 1H), 2.49-2.39 (m, 4H) , 2.38-2.15 (m, 4H), 1.95-1.83 (m, 3H), 1.75 (br. S., 2H), 1.68-1.41 (m, 4H), 1.41-1.23 (m, 1H), 1.04-0.80 (m, 9H); LCMS ( m / z) ES + = 476.2 (M + 1), LCMS (m / z) ES - = 474.1 (M-1).

[Example 50]
(S) -2- (tert-Butoxy) -2- (2-cycloheptyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from cycloheptanone in a manner similar to that described in Example 49 except that the reductive amination was heated to 80 ° C. The final product was isolated as a white solid as a TFA salt after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.34-7.22 (m, 3H), 7.11-6.99 (m, 1H), 5.10-5.03 (m, 1H), 4.49-4.27 (m, 2H), 3.83 -3.70 (m, 1H), 3.69-3.57 (m, 1H), 3.44-3.26 (m, 1H), 3.18-3.04 (m, 2H), 2.43 (s, 3H), 2.38-2.28 (m, 3H) , 2.27-2.09 (m, 2H), 2.03-1.81 (m, 7H), 1.77-1.54 (m, 6H), 1.00-0.84 (m, 9H); LCMS (m / z) ES ⁺ = 478.1 (M + ^{1), ES - = 476.0 (} M-1).

[Example 51]
(S) -2- (tert-Butoxy) -2- (5,8-dimethyl-2- (spiro [2.5] octane-6-yl) -7- (p-tolyl) -1,2,3,4 -Tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from spiro [2.5] octan-6-one in a manner similar to that described in Example 49 and isolated as a formate as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 8.35 (s, 1H), 7.40-7.19 (m, 3H), 7.06 (d, J = 7.7 Hz, 1H), 5.03 (s, 1H), 4.40 ( s, 2H), 3.69-3.55 (m, 2H), 3.49 (t, J = 12.0 Hz, 1H), 3.11 (t, J = 5.9 Hz, 2H), 2.42 (s, 3H), 2.34 (s, 3H ), 2.19 (d, J = 10.4 Hz, 2H), 2.07-1.75 (m, 7H), 1.14 (d, J = 12.8 Hz, 2H), 0.91 (s, 9H), 0.49-0.29 (m, 4H) ; LCMS (m / z) ES ⁺ = 490.6 (M + 1).

[Example 52]
(2S) -2- (tert-butoxy) -2- (2- (3,3-dimethylcyclohexyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline -6-yl) acetic acid

The title compound was made from 3,3-dimethylcyclohexanone in a manner similar to that described in Example 50 and was isolated as a TFA salt as a white solid after reverse phase HPLC (diastereomeric 1: 1 mixture). ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.34-7.21 (m, 3H), 7.06 (t, J = 8.7 Hz, 1H), 5.10-5.04 (m, 1H), 4.45-4.33 (m, 2H ), 3.86 (br. S., 1H), 3.70-3.57 (m, 1H), 3.42-3.01 (m, 3H), 2.43 (s, 3H), 2.38-2.29 (m, 3H), 2.00-1.77 ( m, 5H), 1.76-1.21 (m, 6H), 1.09 (s, 3H), 1.05 (s, 3H), 0.99-0.85 (m, 9H); LCMS (m / z) ES ⁺ = 492.2 (M + ^{1), ES - = 490.1 (} M-1).

[Example 53]
(S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (2- (piperidin-1-yl) acetyl) -7- (p-tolyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from 2- (piperidin-1-yl) acetic acid in a manner similar to that described in Example 5 and isolated as a formate as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, methanol-d ₄ ) (mixture of rotamers) δ ppm 8.40 (br. S., 1H), 7.40-7.20 (m, 3H), 7.06 (d, J = 7.3 Hz, 1H) , 5.03 (s, 1H), 4.75-4.47 (m, 2H), 4.22 (s, 2H), 3.96-3.65 (m, 2H), 3.29-3.11 (m, 4H), 2.98-2.75 (m, 2H) , 2.42 (s, 3H), 2.36-2.22 (m, 3H), 1.96-1.75 (m, 7H), 1.74-1.56 (m, 2H), 0.91 (s, 9H); LCMS (m / z) ES ⁺ = 507.2 (M + 1), ES - = 505.1 (M-1).

[Example 54]
(S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (2-oxo-2- (piperidin-1-yl) ethyl) -7- (p-tolyl) -1, 2,3,4-Tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from 2-chloro-1- (piperidin-1-yl) ethanone in a manner similar to that described in Example 4 and isolated as a formate as a white solid after reverse phase HPLC. did. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 8.37 (br. S., 1H), 7.39-7.20 (m, 3H), 7.06 (d, J = 7.7 Hz, 1H), 5.04 (s, 1H) , 4.23-4.00 (m, 4H), 3.68-3.55 (m, 2H), 3.53-3.42 (m, 2H), 3.40-3.24 (m, 2H), 3.09-2.96 (m, 2H), 2.42 (s, 3H), 2.32 (s, 3H), 1.84 (s, 3H), 1.79-1.52 (m, 6H), 0.92 (s, 9H); LCMS (m / z) ES ⁺ = 507.1 (M + 1), ES ^- = 505.1 (M-1).

[Example 55]
(S) -2- (2-Benzyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2- (tert-butoxy) acetic acid

Step 1: (S) -methyl 2- (2-benzyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2- (tert- Butoxy) acetate

(S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (10 mg, 0.025 mmol) in methanol (0.5 mL) was treated with benzaldehyde (10 μl, 0.099 mmol), acetic acid (10 μl, 0.175 mmol), stirred at room temperature for 1 hour and then heated to 85 ° C. for 18 hours. The reaction was treated with sodium triacetoxyborohydride (8.04 mg, 0.038 mmol) and stirred at room temperature for 4 hours. The mixture was diluted with saturated aqueous NaHCO3, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The resulting pale yellow oil was subjected to the next step without further purification. LCMS (m / z) ES ⁺ = 486.6 (M + 1).

Step 2: (S) -2- (2-benzyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2- (tert-butoxy Acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a formate as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.56-7.31 (m, 6H), 7.24 (t, J = 7.7 Hz, 2H), 7.02 (d, J = 7.7 Hz, 1H), 4.99 (s, 1H), 4.21-4.00 (m, 2H), 3.96-3.78 (m, 2H), 3.23-3.07 (m, 2H), 3.01-2.81 (m, 2H), 2.41 (s, 3H), 2.30 (s, 3H), 1.75 (s, 3H ), 0.89 (s, 9H); LCMS (m / z) ES + = 472.4 (M + 1), ES - = 470.4 (M-1).

[Example 56]
(S) -2- (tert-butoxy) -2- (2- (4,4-difluorocyclohexyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline -6-yl) acetic acid

The title compound was made from 4,4-difluorocyclohexanone in a manner similar to that described in Example 49 and isolated as a TFA salt as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.40-7.17 (m, 3H), 7.06 (d, J = 6.8 Hz, 1H), 5.07 (s, 1H), 4.45 (s, 2H), 3.89 ( br. s., 1H), 3.73-3.55 (m, 1H), 3.50-3.35 (m, 1H), 3.14 (br. s., 2H), 2.43 (s, 3H), 2.38-2.18 (m, 7H ), 2.14 - 1.83 (m, 7H), 0.92 (s, 9H); LCMS (m / z) ES + = 500.5 (M + 1), ES - = 498.4 (M-1).

[Example 57]
(S) -2- (tert-butoxy) -2- (2-((3-fluorophenyl) sulfonyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydro Isoquinolin-6-yl) acetic acid

Step 1: (S) -methyl 2- (tert-butoxy) -2- (2-((3-fluorophenyl) sulfonyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3 , 4-Tetrahydroisoquinolin-6-yl) acetate

(S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (20 mg, 0.051 mmol) in ice-cold dichloromethane (DCM) (1 mL) was treated with pyridine (4.50 μl, 0.056 mmol), 3-fluorobenzene-1-sulfonyl chloride (49.2 mg, 0.253 mmol) and stirred at room temperature for 18 hours. . The reaction was diluted with 1N HCl, extracted with DCM, washed with brine, dried over Na 2 SO 4, filtered and concentrated. Purification by column chromatography (0-50% EtOAc / hexanes) gave the title compound as a white solid. ¹ H NMR (400MHz, chloroform-d) δ ppm 7.66 (d, J = 7.9 Hz, 1H), 7.61-7.49 (m, 2H), 7.35-7.28 (m, 1H), 7.26-7.13 (m, 3H) , 7.02 (d, J = 7.7 Hz, 1H), 5.00 (s, 1H), 4.27-4.06 (m, 2H), 3.66 (s, 3H), 3.51-3.41 (m, 1H), 3.40-3.30 (m , 1H), 2.95-2.76 (m, 2H), 2.42 (s, 3H), 2.25 (s, 3H), 1.80 (s, 3H), 0.94 (s, 9H); LCMS (m / z) ES ⁺ = 576.5 (M + 23, low strength).

Step 2: (S) -2- (tert-butoxy) -2- (2-((3-fluorophenyl) sulfonyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.76-7.55 (m, 3H), 7.47-7.35 (m, 1H), 7.32-7.20 (m, 3H), 7.05 (d, J = 7.9 Hz, 1H ), 5.03 (s, 1H), 4.33-4.10 (m, 2H), 3.58-3.45 (m, 1H), 3.45-3.37 (m, 1H), 2.81 (t, J = 6.0 Hz, 2H), 2.41 ( s, 3H), 2.21 (s , 3H), 1.82 (s, 3H), 0.90 (s, 9H); LCMS (m / z) ES - = 538.3 (M-1).

[Example 58]
(S) -2- (tert-butoxy) -2- (2-((cyclohexylmethyl) sulfonyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline- 6-yl) acetic acid

The title compound was made from cyclohexylmethanesulfonyl chloride in a manner similar to that described in Example 57 except that it was stirred at room temperature and then heated to 45 ° C. The final product was isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.36-7.21 (m, 3H), 7.08 (d, J = 7.1 Hz, 1H), 5.06 (s, 1H), 4.46-4.26 (m, 2H), 3.69-3.47 (m, 2H), 2.97 (d, J = 5.9 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H), 2.42 (s, 3H), 2.29 (s, 3H), 1.98-1.90 (m, 2H), 1.85 ( s, 3H), 1.79 - 1.59 (m, 3H), 1.38 - 1.04 (m, 6H), 0.93 (s, 9H); LCMS (m / z) ES - = 540.4 (M -1).

[Example 59]
(2S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (3-phenylcyclohexyl) -7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6 -Il) Acetic acid

The title compound was made from 3-phenylcyclohexanone in a manner similar to that described in Example 49 and the two diastereomeric mixture was isolated as a TFA salt as a white solid after reverse phase HPLC. Diastereomeric mixture 1: ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.46-7.15 (m, 8H), 7.14-6.97 (m, 1H), 5.07 (s, 1H), 4.43 (s, 2H) , 3.97-3.85 (m, 1H), 3.63-3.51 (m, 1H), 3.50-3.37 (m, 1H), 3.37-3.23 (m, 1H), 3.12 (br. S., 2H), 2.63-2.39 (m, 4H), 2.38-2.24 (m, 4H), 2.21-1.98 (m, 3H), 1.97-1.62 (m, 6H), 1.00-0.84 (m, 9H); LCMS (m / z) ES ⁺ = 540.5 (M + 1), ES - = 538.5 (M-1) diastereomeric mixture ^{2:. 1 H NMR (400MHz} , methanol _{-d 4) δ ppm 7.40 - 7.14} (m, 8H), 7.13 - 6.94 ( m, 1H), 5.12-5.01 (m, 1H), 4.55-4.34 (m, 2H), 4.01-3.81 (m, 1H), 3.77-3.59 (m, 1H), 3.46-3.23 (m, 1H), 3.20-3.02 (m, 2H), 2.78 (t, J = 11.4 Hz, 1H), 2.50-2.07 (m, 9H), 2.01-1.45 (m, 8H), 1.08-0.76 (m, 9H); LCMS ( ^{m / z) ES + = 540.5} (M + 1), ES - = 538.5 (M-1).

[Example 60]
(2S) -2- (2- (Bicyclo [3.2.1] octan-2-yl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6- Yl) -2- (tert-butoxy) acetic acid

Step 1: (2S) -methyl 2- (2- (bicyclo [3.2.1] octane-2-yl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydro Isoquinolin-6-yl) -2- (tert-butoxy) acetate

(S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (20 mg, 0.051 mmol) in 1,2-dichloroethane (DCE) (1 mL) was treated with bicyclo [3.2.1] octan-2-one (9.42 mg, 0.076 mmol) and stirred at room temperature for 15 min. The reaction was treated with sodium triacetoxyborohydride (16.08 mg, 0.076 mmol) and stirred at room temperature for 18 hours and then heated to 50 C for 3 hours. The reaction was treated with acetic acid (10 μl, 0.175 mmol), stirred at room temperature for 2 hours, heated to 50 C for 2 hours, then cooled to room temperature over the weekend. The reaction was treated with titanium (IV) isopropoxide (100 μl, 0.341 mmol), sodium cyanoborohydride (4.77 mg, 0.076 mmol) and stirred at room temperature for 5 hours. The mixture was diluted with saturated aqueous NaHCO3, extracted with DCM, washed with brine, dried over Na2SO4, filtered and concentrated to crude (2S) -methyl 2- (2- (bicyclo [3.2.1] Octan-2-yl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2- (tert-butoxy) acetate (16.1 mg, 0.032 mmol, 63.2% yield) was obtained as a turbid oil. LCMS (m / z) ES ⁺ = 504.6 (M + 1).

Step 2: (2S) -2- (2- (bicyclo [3.2.1] octan-2-yl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline -6-yl) -2- (tert-butoxy) acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4. After reverse phase HPLC, a 1: 1 mixture of diastereomers as a TFA salt was isolated as a white solid. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.35-7.21 (m, 3H), 7.13-7.00 (m, 1H), 5.07 (s, 1H), 4.64-4.22 (m, 2H), 4.09-3.94 (m, 1H), 3.55-3.38 (m, 1H), 3.37-3.19 (m, 1H), 3.18-3.02 (m, 2H), 2.92-2.73 (m, 1H), 2.43 (s, 3H), 2.39 -2.14 (m, 5H), 2.09-1.94 (m, 1H), 1.90 (br. S., 3H), 1.87-1.43 (m, 8H), 1.01-0.84 (m, 9H); LCMS (m / z ^{) ES + = 490.5 (M +} 1), ES - = 488.5 (M-1).

[Example 61]
(S) -2- (tert-Butoxy) -2- (2-cyclobutyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: (S) -methyl 2- (tert-butoxy) -2- (2-cyclobutyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6- Yl) acetate

(S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (20 mg, 0.051 mmol) in 1,2-dichloroethane (DCE) (1 mL) was treated with cyclobutanone (17.72 mg, 0.253 mmol) and stirred at room temperature for 15 min. The reaction was treated with sodium triacetoxyborohydride (16.08 mg, 0.076 mmol) and stirred at room temperature for 18 hours. The reaction was heated to 50 ° C. for 3 hours. The reaction was treated with acetic acid (10 μl, 0.175 mmol) and stirred at room temperature for 2 hours and then at 50 ° C. for 1.5 hours. The reaction was treated with additional cyclobutanone (57 mg), sodium triacetoxyborohydride (16.08 mg, 0.076 mmol), stirred at 50 ° C. for 1 hour, then cooled to room temperature over the weekend. The mixture was diluted with saturated aqueous NaHCO3, extracted with DCM, washed with brine, dried over Na2SO4, filtered and concentrated to give 26 mg of crude product. Purify by column chromatography (0-100% EtOAc / hexanes) and mix the (S) -methyl 2- (tert-butoxy) -2- (2-cyclobutyl-5,8-dimethyl-7- (p-Tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (9.2 mg, 0.020 mmol, 40.5% yield) was obtained as a non-turbid film. LCMS (m / z) ES ⁺ = 450.6 (M + 1).

Step 2: (S) -2- (tert-butoxy) -2- (2-cyclobutyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl Acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a TFA salt as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.35-7.21 (m, 3H), 7.13-7.00 (m, 1H), 5.07 (br. S., 1H), 4.41 (d, J = 15.4 Hz, 1H), 4.07 (d, J = 15.4 Hz, 1H), 3.91 (quintage, J = 8.1 Hz, 1H), 3.82-3.66 (m, 1H), 3.26-2.98 (m, 3H), 2.57-2.25 (m, 10H), 2.03 - 1.84 (m, 5H), 0.92 (br s, 9H..); LCMS (m / z) ES + = 436.4 (M + 1), ES - = 434.4 (M-1) .

[Example 62]
(S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (neopentylsulfonyl) -7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6- Yl) acetic acid

Step 1: (S) -methyl 2- (tert-butoxy) -2- (5,8-dimethyl-2- (neopentylsulfonyl) -7- (p-tolyl) -1,2,3,4-tetrahydro Isoquinolin-6-yl) acetate

(S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (20 mg, 0.051 mmol) in ice-cold dichloromethane (DCM) (1 mL) was treated with pyridine (4.50 μl, 0.056 mmol), 2,2-dimethylpropane-1-sulfonyl chloride (43.1 mg, 0.253 mmol) and at room temperature for 18 hours. Stir. The reaction was heated to 50 ° C. for 2 hours, treated with additional pyridine (10 uL), 2,2-dimethylpropane-1-sulfonyl chloride (43.1 mg, 0.253 mmol) and stirred at 50 ° C. for 1 hour. The reaction was treated with DMAP (3.09 mg, 0.025 mmol), Et3N (0.014 mL, 0.101 mmol) and stirred at 50 ° C. for 1.5 hours. The mixture was cooled to room temperature, diluted with 1N HCl, extracted with DCM, washed with brine, dried over Na 2 SO 4, filtered and concentrated. Purify by column chromatography (0-70% EtOAc / hexane) to obtain (S) -methyl 2- (tert-butoxy) -2- (5,8-dimethyl-2- (neopentylsulfonyl) -7- ( p-Tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (6.9 mg, 0.013 mmol, 25.8% yield) was obtained as a non-turbid film. LCMS (m / z) ES ⁺ = 530.6 (M + 1, low intensity), 552.5 (M + 23).

Step 2: (S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (neopentylsulfonyl) -7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline -6-yl) acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.37-7.20 (m, 3H), 7.08 (d, J = 7.7 Hz, 1H), 5.07 (s, 1H), 4.47-4.23 (m, 2H), 3.62-3.54 (m, 1H), 3.53-3.44 (m, 1H), 3.00 (s, 2H), 2.88 (t, J = 5.8 Hz, 2H), 2.42 (s, 3H), 2.29 (s, 3H) , 1.86 (s, 3H), 1.19 (s, 9H), 0.93 (s, 9H); LCMS (m / z) ES - = 514.4 (M-1).

[Example 63]
(S) -2- (tert-Butoxy) -2- (2- (N-cyclohexylsulfamoyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline -6-yl) acetic acid

The title compound was made from cyclohexylsulfamoyl chloride in a manner similar to that described in Example 57 except that it was heated to 50 ° C. The final product was isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.35-7.19 (m, 3H), 7.07 (d, J = 7.5 Hz, 1H), 5.06 (s, 1H), 4.32-4.17 (m, 2H), 3.56-3.39 (m, 2H), 3.18-3.03 (m, 1H), 2.85 (t, J = 5.8 Hz, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 1.93 (br. S. , 2H), 1.84 (s, 3H), 1.79 - 1.52 (m, 3H), 1.35 - 1.09 (m, 5H), 0.92 (s, 9H); LCMS (m / z) ES - = 541.4 (M-1 ).

[Example 64]
(S) -2- (tert-butoxy) -2- (2-((3-fluoro-2-methoxyphenyl) sulfonyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3 , 4-Tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from 3-fluoro-2-methoxy-benzene-1-sulfonyl chloride in a manner similar to that described in Example 57 except that it was heated to 45-55 ° C. The final product was isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.72 (d, J = 7.7 Hz, 1H), 7.49-7.36 (m, 1H), 7.32-7.18 (m, 4H), 7.06 (d, J = 7.7 Hz, 1H), 5.04 (s, 1H), 4.48-4.25 (m, 2H), 3.96 (s, 3H), 3.75-3.46 (m, 2H), 2.75 (t, J = 5.9 Hz, 2H), 2.41 (s, 3H), 2.21 ( s, 3H), 1.80 (s, 3H), 0.91 (s, 9H); LCMS (m / z) ES - = 568.3 (M-1).

[Example 65]
(S) -2- (tert-Butoxy) -2- (2- (cyclopentylsulfonyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl Acetic acid

Step 1: (S) -methyl 2- (tert-butoxy) -2- (2- (cyclopentylsulfonyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline -6-yl) acetate

(S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (20 mg, 0.051 mmol) in ice-cold dichloromethane (DCM) (1 mL) was treated with pyridine (4.50 μl, 0.056 mmol), cyclopentanesulfonyl chloride (42.6 mg, 0.253 mmol) and stirred at room temperature for 4.5 hours. The reaction was heated at 45 ° C. for 1 hour, treated with additional pyridine (10 uL), stirred at 55 ° C. for 18 hours, and cooled to room temperature over the weekend. The mixture was treated with DMAP (3.09 mg, 0.025 mmol), stirred for 1.5 hours, treated with Et3N (0.014 mL, 0.101 mmol) and stirred at 50 ° C. for 2.5 hours. The reaction was cooled to room temperature, diluted with 1N HCl, extracted with DCM, washed with brine, dried over Na 2 SO 4, filtered and concentrated. Purify by column chromatography (0-50% EtOAc / hexanes) to give (S) -methyl 2- (tert-butoxy) -2- (2- (cyclopentylsulfonyl) -5,8-dimethyl-7- (p -Tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (9.7 mg, 0.018 mmol, 36.4% yield) was obtained as a white solid. LCMS (m / z) ES ⁺ = 550.5 (M + 23, low intensity).

Step 2: (S) -2- (tert-butoxy) -2- (2- (cyclopentylsulfonyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline- 6-yl) acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.34-7.21 (m, 3H), 7.08 (d, J = 7.3 Hz, 1H), 5.06 (s, 1H), 4.50-4.32 (m, 2H), 3.80-3.55 (m, 3H), 2.85 (t, J = 5.9 Hz, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 2.12-1.89 (m, 4H), 1.85 (s, 3H) , 1.82 - 1.57 (m, 4H ), 0.92 (s, 9H); LCMS (m / z) ES - = 512.4 (M-1).

[Example 66]
(S) -2- (tert-Butoxy) -2- (2- (isopropylsulfonyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl Acetic acid

The title compound was made from propane-2-sulfonyl chloride in a manner similar to that described in Example 57, except that it was heated to 45-55 ° C. The final product was isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.36-7.20 (m, 3H), 7.08 (d, J = 7.1 Hz, 1H), 5.06 (s, 1H), 4.51-4.34 (m, 2H), 3.78-3.55 (m, 2H), 3.50-3.37 (m, 1H), 2.85 (t, J = 5.8 Hz, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 1.84 (s, 3H) , 1.39 - 1.27 (m, 6H ), 0.92 (s, 9H); LCMS (m / z) ES - = 486.4 (M-1).

[Example 67]
(2S) (M) -2- (tert-Butoxy) -2- (2-cyclohexyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1,2,3 , 4-Tetrahydroisoquinolin-6-yl) acetic acid

Step 1: 4-methoxy-2,5-dimethylbenzaldehyde

DMF (50 mL) solution of 4-hydroxy-2,5-dimethyl-benzaldehyde (10.0 g, 66.6 mmol) to a stirred solution of methyl iodide (4.37 mL, 69.9 mmol), followed by K ₂ CO ₃ (18.4g, 133mmol ) Was added. The resulting mixture was stirred at room temperature. After 1.5 hours, TLC (silica gel, 75:25 hexanes / EtOAc) showed that the starting material was completely converted to a new component with a higher R _f . The mixture was partitioned between water and EtOAc and the phases separated. The aqueous solution was extracted once with EtOAc. The combined EtOAc solution was washed with water (2 times), brine (1 time), dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure to give the title compound (10.7 g, 98%) as a pale yellow Obtained as a liquid. ¹ H NMR (400 MHz, CDCl ₃ ) δ
10.13 (s, 1H), 7.59 (s, 1H), 6.65 (s, 1H), 3.90 (s, 3H), 2.66 (s, 3H), 2.22 (s, 3H). LCMS (ES +) (m / z ): 165.21 (M + 1).

Step 2: (E) -1-methoxy-2,5-dimethyl-4- (2-nitrovinyl) benzene

To a solution of 4-methoxy-2,5-dimethylbenzaldehyde (10.6 g, 64.6 mmol) in glacial AcOH (52 mL) was added nitromethane (10.4 mL, 194 mmol) followed by NH ₄ OAc (1.99 g, 25.8 mmol). The resulting solution was heated to reflux under nitrogen. After 18 hours, the solution was cooled to room temperature, at which point a solid formed. The mixture was diluted with water (250 mL). The resulting suspension was stirred vigorously for 30 minutes. The solid was collected by filtration and washed twice with water. The solid was aspirated and air dried for 1 hour, then dried in vacuo for 2 hours to give 12.0 g of an orange-brown solid. This material was recrystallized from hot hexane / EtOAc to give the title compound (8.89 g, 67%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.26 (d, J = 13.5 Hz, 1H), 7.49 (d, J = 13.5 Hz, 1H), 7.32 (s, 1H), 6.69 (s, 1H), 3.88 (s, 3H), 2.47 (s, 3H), 2.19 (s, 3H).

Step 3: 2- (4-Methoxy-2,5-dimethylphenyl) ethanamine

A solution of (E) -1-methoxy-2,5-dimethyl-4- (2-nitrovinyl) benzene (8.80 g, 42.5 mmol) in anhydrous THF (65 mL) was added to 1M BH ₃ / THF (212 mL, 212 mmol). Slowly added over a minute. The resulting solution was heated to reflux with stirring under nitrogen. After 3 hours, the solution was cooled to room temperature and stirred overnight. The solution was cooled to 0 ° C. and treated with 6M aqueous HCl (142 mL, 849 mmol) by slow addition over 10 minutes. The mixture was diluted with water and stirred at room temperature for 30 minutes. The solution was extracted with ether (3 times). The aqueous solution was cooled in an ice-water bath and slowly treated with 10M aqueous NaOH (106 mL, 1062 mmol). The resulting cloudy solution was extracted with ether (3 times). The combined ether extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (6.94 g, 91%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.91 (s, 1H), 6.64 (s, 1H), 3.81 (s, 3H), 2.85-2.94 (m, 2H), 2.63-2.74 (m, 2H), 2.30 (s, 3H), 2.18 (s, 3H), 1.24-1.61 (br s, 2 H). LCMS (ES +) (m / z): 180.26 (M + 1).

Step 4: methyl 4-methoxy-2,5-dimethylphenethylcarbamate

A stirred solution of 2- (4-methoxy-2,5-dimethylphenyl) ethanamine (6.94 g, 38.78 mmol) and DIEA (10.1 mL, 58.1 mmol) in DCM (51 mL) was added dropwise at 0 ° C. with chloroform. Treated with methyl acid (3.00 mL, 38.7 mmol). After 30 minutes, LCMS indicated that the reaction was complete. The solution was concentrated to dryness and the residue was dissolved in EtOAc. The solution was washed with 10% aqueous citric acid (2 times), saturated aqueous NaHCO ₃ (2 times), dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure to give the title compound in quantitative yield. . ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.88 (s, 1H), 6.64 (s, 1H), 4.72 (br s, 1H), 3.81 (s, 3H), 3.68 (s, 3H), 3.35 (m , 2H), 2.74 (m, 2H), 2.31 (s, 3H), 2.17 (s, 3H). LCMS (ES +) (m / z): 238.32 (M + 1).

Step 5: 7-methoxy-5,8-dimethyl-3,4-dihydroisoquinolin-1 (2H) -one

Polyphosphoric acid (30 g) was added to methyl 4-methoxy-2,5-dimethylphenethylcarbamate (9.10 g, 38.3 mmol) and the mixture was heated to 100 ° C. with slow stirring. The reaction progress was monitored by LCMS. After 2.5 hours, the reaction temperature was raised to 110 ° C. After an additional 1.5 hours, LCMS indicated that the reaction was complete. The mixture was cooled to about 60 ° C. and the residue was dissolved in 1: 1 EtOAc / water. The resulting biphasic mixture was stirred vigorously for 30 minutes and then the phases were separated. The aqueous phase was extracted twice with additional portions of EtOAc. The combined EtOAc solution was washed with saturated aqueous NaHCO ₃ solution (2 times), brine (1 time), dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure to give a gray solid. This material was triturated with hexane, filtered and dried in vacuo to give the title compound (3.87 g, 49%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.82 (s, 1H), 6.30 (br s, 1H), 3.83 (s, 3H), 3.43 (m, 2H), 2.81 (m, 2H), 2.55 (s , 3H), 2.30 (s, 3H). LCMS (ES +) (m / z): 206.27 (M + 1).

Step 6: 7-methoxy-5,8-dimethyl-1,2,3,4-tetrahydroisoquinoline

Under nitrogen, 1M LAH / THF (56.4 mL, 56.4 mmol) was added to anhydrous THF (70 mL). The solution was cooled to 0 ° C. and added dropwise with 7-methoxy-5,8-dimethyl-3,4-dihydroisoquinolin-1 (2H) -one (3.86 g, 18.8 mmol) in anhydrous THF (80 mL). Processed. The resulting solution was heated to reflux with stirring. After 2.5 hours, the cloudy solution was cooled to 0 ° C. and quenched by the dropwise addition of water (2.1 mL), then 15% aqueous NaOH (2.1 mL), then water (6.3 mL). After warming to room temperature and stirring for 1 h, celite was added and the mixture was filtered and washed with excess EtOAc. The filtrate was concentrated under reduced pressure to give the title compound (3.56 g, 99%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.65 (s, 1H), 3.66-3.76 (m, 5H), 2.89 (t, J = 5.9 Hz, 2H), 2.45 (t, J = 5.8 Hz, 2H), 2.13 (s, 3H), 1.93 (s, 3H). LCMS (ES +) (m / z): 192.08 (M + 1).

Step 7: 5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-ol hydrobromide

A suspension of 7-methoxy-5,8-dimethyl-1,2,3,4-tetrahydroisoquinoline (3.56 g, 18.6 mmol) in 48% aqueous HBr (50 mL) was stirred under nitrogen under 100%. Heated to ° C. After 18 hours, the mixture was cooled to room temperature. The suspension was then cooled to 0 ° C. and stirred for 1 hour, and the solid was collected by vacuum filtration. The filter cake was washed with ice cold water (2 times), ether (1 time) and dried in vacuo to give the title compound (4.34 g, 90%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.20 (s, 1H), 9.03 (br s, 2H), 6.65 (s, 1H), 4.12 (br s, 2H), 3.25-3.41 (m, 2H ), 2.73 (t, J = 6.1 Hz, 2H), 2.10 (s, 3H), 1.96 (s, 3H). LCMS (ES +) (m / z): 178.24 (M + 1).

Step 8: benzyl 7-hydroxy-5,8-dimethyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate

Stirring of 5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-ol hydrobromide (4.34 g, 16.8 mmol) and DIEA (4.40 mL, 25.2 mmol) in THF (80 mL) To the suspension, CbzCl (2.40 mL, 16.8 mmol) was added dropwise at 0 ° C. The reaction mixture was warmed to room temperature. After 30 minutes, LCMS indicated that the reaction was complete. The suspension was partitioned between 0.5M aqueous HCl and EtOAc and the phases separated. The EtOAc solution was washed with water (2 times), brine (1 time), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was subjected to flash chromatography (silica gel, 0-70% EtOAc / hexanes, gradient elution) to give the title compound (4.02 g, 77%) as a white foam. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 7.26-7.44 (m, 5H), 6.55 (s, 1H), 5.13 (s, 2H), 4.36-4.51 (m, 2H ), 3.60 (br s, 2H), 2.55 (t, J = 5.9 Hz, 2H), 2.07 (s, 3H), 1.86-2.00 (m, 3H). LCMS (ES +) (m / z): 312.31 ( M + 1).

Step 9: 5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-ol

A solution of benzyl 7-hydroxy-5,8-dimethyl-3,4-dihydroisoquinoline-2 (1H) -carboxylate (4.02 g, 12.9 mmol) in MeOH (150 mL) was added 10% Pd / C (0.40 g). In the presence, it was subjected to hydrogenation at 40 psi. After 2 hours, LCMS showed the reaction was complete and the product precipitated. To remove the catalyst, the mixture was diluted with MeOH (100 mL) and DCM (100 mL) and heated to reflux under nitrogen until all solid product was dissolved. The catalyst was removed by filtration through Celite and the filtrate was concentrated to dryness under reduced pressure to give the title compound (2.24 g, 98%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (br s, 1H), 6.48 (s, 1H), 3.68 (s, 2H), 2.88 (t, J = 5.8 Hz, 2H), 2.41 (t , J = 5.7 Hz, 2H), 2.04 (s, 3H), 1.90 (s, 3H). LCMS (ES +) (m / z): 178.23 (M + 1).

Step 10: 2,2,2-trifluoro-1- (7-hydroxy-5,8-dimethyl-3,4-dihydroisoquinolin-2 (1H) -yl) ethanone

To a stirred suspension of 5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-ol (2.24 g, 12.6 mmol) in anhydrous DCM (65 mL) at −10 ° C. DIEA (2.65 mL). , 15.2 mmol). After this, a solution of trifluoroacetic anhydride (1.80 mL, 12.6 mmol) in DCM (8 mL) was added dropwise over 5 minutes. After stirring at −10 ° C. for 1 hour, LCMS showed the reaction was complete. The solution was diluted with DCM, washed with 1N aqueous HCl (2 ×), water (1 ×), dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure. The crude product was recrystallized from hot hexane / EtOAc to give the title compound (2.18 g, 63%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ , mixture of rotamers) δ 9.04-9.18 (m, 1H), 6.50-6.64 (m, 1H), 4.60 (s, 2H), 3.71-3.83 (m, 2H), 2.60-2.72 (m, 2H), 1.90-2.16 (m, 6H). LCMS (ES +) (m / z): 274.26 (M + 1).

Step 11: (S)-(1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2-hydroxy-2- (7-hydroxy-5,8-dimethyl-2- (2,2,2-tri Fluoroacetyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

2,2,2-Trifluoro-1- (7-hydroxy-5,8-dimethyl-3,4-dihydroisoquinolin-2 (1H) -yl) ethanone (1.98 g, 7.25 mmol) in anhydrous DCM (65 mL) 1M TiCl _{4 /} DCM (8.70 mL, 8.70 mmol) was added at 0 ° C. to the stirred solution over 5 minutes. A dark red-brown solution formed and was stirred at 0 ° C. After 10 minutes, a solution of (1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2-oxoacetate (2.46 g, 11.6 mmol) in DCM (20 mL) was added dropwise. The resulting mixture was stirred at 0 ° C. After 1.5 hours, LCMS showed complete conversion to the desired product. The mixture was partitioned between DCM and 1N aqueous HCl and the phases were separated. The aqueous phase was extracted with DCM (2 times). The combined DCM solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was subjected to flash chromatography (silica gel, 0-100% EtOAc / hexanes, gradient elution) to give the title compound as a light tan foam in quantitative yield. ¹ H NMR (400 MHz, DMSO-d ₆ , mixture of rotamers) δ 8.62-8.76 (m, 1H), 5.56-6.66 (m, 2H), 4.50-4.68 (m, 3H), 3.66-3.88 ( m, 2H), 2.63-2.82 (m, 2H), 0.57-2.23 (m, 24H). LCMS (ES +) (m / z): 486.48 (M + 1).

Step 12: (S)-(1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2- (7-hydroxy-5,8-dimethyl-2- (2,2,2-trifluoroacetyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl) -2-((triethylsilyl) oxy) acetate

(S)-(1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2-hydroxy-2- (7-hydroxy-5,8-dimethyl-2- (2,2) in anhydrous DCM (48 mL) , 2-trifluoroacetyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (3.50 g, 7.21 mmol) and imidazole (0.74 g, 10.8 mmol) in TES at 0 ° C. A solution of -Cl (1.10 mL, 6.49 mmol) in DCM (5 mL) was added dropwise. This resulted in a white suspension that was stirred at 0 ° C. After 30 minutes, LCMS showed about 50% conversion. This solution was treated with additional imidazole (0.25 g, 0.50 equiv) and TES-Cl (0.363 mL, 0.30 equiv) in DCM (2 mL) and stirring was continued at 0 ° C. After another 30 minutes, an additional 0.363 mL of TES-Cl was added. After an additional 30 minutes, the mixture was partitioned between 1N aqueous HCl and DCM and the phases separated. The aqueous phase was extracted with one additional portion of DCM. The combined DCM solution was washed with 1N HCl (1 ×), brine (1 ×), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was subjected to flash chromatography (silica gel, 0-70% EtOAc / hexanes, gradient elution) to give the title compound (3.59 g, 83%) as a white sticky foam. ¹ H NMR (400 MHz, DMSO-d ₆ , mixture of rotamers) δ 8.37-8.51 (m, 1H), 5.96 (br s, 1H), 4.52-4.71 (m, 3H), 3.71-3.89 (m , 2H), 2.61-2.82 (m, 2H), 2.00-2.16 (m, 6H), 1.74-1.95 (m, 2H), 1.61 (m, 2H), 1.24-1.52 (m, 2H), 0.45-1.14 (m, 27H). LCMS (ES +) (m / z): 622.67 (M + Na).

Step 13: (S)-(1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2- (5,8-dimethyl-2- (2,2,2-trifluoroacetyl) -7-(( (Trifluoromethyl) sulfonyl) oxy) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2-((triethylsilyl) oxy) acetate

(S)-(1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2- (7-hydroxy-5,8-dimethyl-2- (2,2,2-tri) in anhydrous DCM (60 mL) A stirred solution of fluoroacetyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2-((triethylsilyl) oxy) acetate (3.55 g, 5.92 mmol) and TEA (2.06 mL, 14.8 mmol) Was added dropwise at −78 ° C. with 1M trifluoromethanesulfonic anhydride / DCM (7.40 mL, 7.40 mmol). After 1 hour, LCMS indicated that the reaction was complete. The solution was partitioned between 1N aqueous HCl and DCM and the phases were separated. The aqueous solution was extracted with one additional portion of DCM. The combined DCM solution was washed with 1N aqueous HCl (once), brine (once), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was subjected to flash chromatography (silica gel, 0-15% EtOAc / hexanes, gradient elution) to give the title compound (4.00 g, 92%) as a white foam. ¹ H NMR (400 MHz, DMSO-d ₆ , mixture of rotamers) δ 5.58-5.81 (m, 1H), 4.58-4.82 (m, 3H), 3.71-3.97 (m, 2H), 2.73-2.96 ( m, 2H), 2.15-2.24 (m, 7H), 1.91-2.00 (m, 1H), 1.76-1.83 (m, 1H), 1.57-1.66 (m, 2H), 1.26-1.36 (m, 1H), 0.78-0.92 (m, 18H), 0.71 (d, J = 7.0 Hz, 3H), 0.47-0.63 (m, 6H). LCMS (ES +) (m / z): 754.64 (M + Na).

Step 14: (S)-(1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2- (5,8-dimethyl-2- (2,2,2-trifluoroacetyl) -7-(( (Trifluoromethyl) sulfonyl) oxy) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2-hydroxyacetate

(S)-(1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2- (5,8-dimethyl-2- (2,2,2-trifluoro) in THF (50 mL) in a Teflon container Acetyl) -7-(((trifluoromethyl) sulfonyl) oxy) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2-((triethylsilyl) oxy) acetate (4.00 g, 5.47 mmol) A 48% aqueous HF solution was added to the stirred solution. The resulting solution was stirred at room temperature. After 18 hours, LCMS indicated that the reaction was complete. The solution was diluted with EtOAc, washed with saturated aqueous NaHCO ₃ (3 times), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was subjected to flash chromatography (silica gel, 0-100% EtOAc / hexanes, gradient elution) to give the title compound (3.12 g, 92%) as a white foam. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.36-6.45 (m, 1H), 5.46 (d, J = 4.9 Hz, 1H), 4.56-4.81 (m, 3H), 3.69-3.97 (m, 2H ), 2.71-2.93 (m, 2H), 2.12-2.26 (m, 6H), 1.71-1.93 (m, 2H), 1.54-1.65 (m, 2H), 1.34-1.50 (m, 1H), 1.19-1.31 (m, 1H), 0.61-1.09 (m, 12H). LCMS (ES +) (m / z): 635.56 (M + 18).

Step 15: (S)-(1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2- (tert-butoxy) -2- (5,8-dimethyl-2- (2,2,2-tri Fluoroacetyl) -7-(((trifluoromethyl) sulfonyl) oxy) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

(S)-(1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2- (5,8-dimethyl-2- (2,2,2-trifluoroacetyl) in t-BuOAc (20 mL) To a stirred solution of -7-((((trifluoromethyl) sulfonyl) oxy) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2-hydroxyacetate (0.250 g, 0.41 mmol) Acid (49 uL, 0.81 mmol) was added. After 50 minutes, the solution was poured into rapidly stirred saturated aqueous NaHCO ₃ solution. After stirring for a few minutes, the phases were separated. The aqueous solution was extracted once with EtOAc. The combined organic solution was washed with saturated aqueous NaHCO ₃ solution (1 ×), dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was subjected to flash chromatography (silica gel, 0-50% EtOAc / hexanes) to give the title compound as a white foam (0.214 g, 78%). ¹ H NMR (400MHz, chloroform-d) δ = 5.60-5.50 (m, 1H), 4.89-4.51 (m, 3H), 4.16-3.66 (m, 2H), 2.98-2.68 (m, 2H), 2.33- 2.19 (m, 6H), 2.12-1.83 (m, 2H), 1.66 (d, J = 11.9 Hz, 2H), 1.52-1.30 (m, 2H), 1.26-1.13 (m, 10H), 1.11-0.97 ( m, 1H), 0.88 (t, J = 6.0 Hz, 7H), 0.76 (d, J = 6.8 Hz, 3H); LC / MS (m / z) ES ⁺ = 696 (M + 23).

Step 16: (S)-(1S, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman- 6-yl) -5,8-dimethyl-2- (2,2,2-trifluoroacetyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

(S)-(1S, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2- (tert-butoxy) -2- (5,8-dimethyl-2) in 1,2-dimethoxyethane (1.0 mL) -(2,2,2-trifluoroacetyl) -7-(((trifluoromethyl) sulfonyl) oxy) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (50.0 mg, 0.074 mmol) A degassed mixture of (8-fluoro-5-methylchroman-6-yl) boronic acid (39.0 mg, 0.186 mmol) and CsF (64.0 mg, 0.421 mmol) (2-dicyclohexylphosphino-2 ′, 6 Treatment with '-dimethoxy-1,1'-biphenyl) [2- (2-aminoethylphenyl)] palladium (II) chloride-methyl-t-butyl ether adduct (16.94 mg, 0.022 mmol) and a few more minutes Degassed and then the mixture was irradiated with microwave at 130 ° C. for 40 minutes. Add additional CsF (80 mg), (8-fluoro-5-methylchroman-6-yl) boronic acid (39.0 mg, 0.186 mmol), and finally Pd S-phos precatalyst (16.94 mg, 0.022 mmol). The mixture was degassed. The mixture was irradiated with microwaves at 130 ° C. for 30 minutes. LCMS showed that the starting material was completely consumed. The crude reaction mixture was left for processing with additional batches. Two additional experiments were similarly performed with 31 mg and 84 mg of triflate starting material using either 1,2-dimethoxyethane or 1,4-dioxane as the solvent. When the reaction was complete, the crude reaction mixtures were combined and diluted with EtOAc, washed with water, then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g column, 0-15% hexane / EtOAc gradient elution) to give the title compound as a pale yellow residue (31 mg, 18%). 1H NMR showed a 9: 1 mixture of diastereomers. LC / MS (m / z) ES ⁺ = 712 (M + 23).

Step 17: (S)-(1S, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman- 6-yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

(S)-(1S, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl ) -5,8-dimethyl-2- (2,2,2-trifluoroacetyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (31.0 mg, 0.045 mmol) in methanol (0.8 mL The solution was treated with potassium carbonate (3.60 mg, 0.026 mmol) and the mixture was stirred at ambient temperature for 7 hours. The mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a pale yellow residue (28 mg) that was used in the next step without purification. LC / MS (m / z) ES ⁺ = 594 (M + 1).

Step 18: (S)-(1S, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2- (tert-butoxy) -2-((R) -2-cyclohexyl-7- (8-fluoro-5 -Methylchroman-6-yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Crude (S)-(1S, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2- (tert-butoxy) -2-((R) -7- () in 1,2-dichloroethane (0.8 mL) A mixture of 8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (28 mg, 0.046 mmol) was added to cyclohexanone (7.45 μl, 0.072 mmol) followed by sodium triacetoxyborohydride (19.05 mg, 0.090 mmol) and the mixture was stirred overnight at ambient temperature. The mixture was diluted with EtOAc, washed with saturated sodium bicarbonate, then brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give a pale yellow residue (19 mg, 63%). LC / MS (m / z) ES ⁺ = 676 (M + 1).

Step 19: (S) -2- (tert-butoxy) -2-((R) -2-cyclohexyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1 , 2,3,4-Tetrahydroisoquinolin-6-yl) acetic acid

(S)-(1S, 2S, 5R) -2-isopropyl-5-methylcyclohexyl 2- (tert-butoxy) -2-((R) -2-) in ethanol (0.5 mL) and tetrahydrofuran (0.5 mL) A solution of cyclohexyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (19 mg, 0.028 mmol) Treated with 2M LiOH (0.5 mL). The mixture was heated at 80 ° C. for 1 h, after which time LCMS showed no reaction. The mixture was transferred to a microwave vial and irradiated with microwaves at 100-140 ° C. for 10 hours at intervals of 10-30 minutes. Intermittently, the reaction mixture was treated with 50% NaOH (230 uL, added in 3 portions) and MeOH (600 uL, added in 2 portions). The mixture was concentrated under reduced pressure. Water was added and the mixture was adjusted to about pH 7 with 1N HCl. The resulting mixture was extracted with EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC to give the title compound as a white solid (5.3 mg, 35%). ¹ H NMR (400MHz, chloroform-d) δ = 6.63 (d, J = 11.5 Hz, 1H), 4.85-4.13 (m, 3H), 3.85-3.75 (m, 1H), 3.50 (s, 1H), 2.84 -2.53 (m, 4H), 2.34 (s, 3H), 2.19-1.94 (m, 4H), 1.90-1.78 (m, 2H), 1.74-1.47 (m, 6H), 1.44-0.99 (m, 18H) ; LC / MS (m / z) ES ⁺ = 538 (M + 1).

[Example 68]
(S) -2- (tert-butoxy) -2- (2- (cycloheptylsulfonyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6- Yl) acetic acid

The title compound was made from cycloheptanesulfonyl chloride in a manner similar to that described in Example 57 except that it was heated to 50 ° C. The final product was isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.38-7.20 (m, 3H), 7.08 (d, J = 7.3 Hz, 1H), 5.06 (s, 1H), 4.53-4.32 (m, 2H), 3.76-3.54 (m, 2H), 3.42-3.22 (m, 1H), 2.93-2.74 (m, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 2.23-2.08 (m, 2H), 1.94 - 1.73 (m, 7H) , 1.69 - 1.45 (m, 6H), 0.93 (s, 9H); LCMS (m / z) ES - = 540.4 (M-1).

[Example 69]
(S) -2- (tert-Butoxy) -2- (2-cyclooctyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: (S) -Methyl 2- (tert-butoxy) -2- (2-cyclooctyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6 -Il) Acetate

(S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (20 mg, 0.051 mmol) in 1,2-dichloroethane (DCE) (1 mL) was treated with cyclooctanone (9.57 mg, 0.076 mmol) and stirred at room temperature for 15 min. The reaction was treated with sodium triacetoxyborohydride (16.08 mg, 0.076 mmol) and stirred at room temperature for 18 hours. The reaction was treated with additional cyclooctanone (9.57 mg, 0.076 mmol), sodium triacetoxyborohydride (16.08 mg, 0.076 mmol) and stirred at room temperature for 1.5 hours. The mixture was treated with acetic acid (5.79 μl, 0.101 mmol), stirred at room temperature for 1.5 hours, then heated to 50 ° C. for 2.5 hours. The reaction was cooled to room temperature, diluted with saturated aqueous NaHCO3, extracted with DCM, washed with brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography (0-100% EtOAc / hexanes) gave the title compound (8 mg, 0.016 mmol, 31.3% yield) as a non-turbid film. LCMS (m / z) ES ⁺ = 506.6 (M + 1).

Step 2: (S) -2- (tert-butoxy) -2- (2-cyclooctyl-5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6- Yl) acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a TFA salt as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.37-7.21 (m, 3H), 7.12-6.97 (m, 1H), 5.11-5.01 (m, 1H), 4.49-4.27 (m, 2H), 3.83 -3.65 (m, 2H), 3.46-3.34 (m, 1H), 3.18-3.01 (m, 2H), 2.43 (s, 3H), 2.38-2.25 (m, 3H), 2.19-1.85 (m, 9H) , 1.79 - 1.47 (m, 8H ), 1.00 - 0.81 (m, 9H); LCMS (m / z) ES + = 492.5 (M + 1), ES - = 490.4 (M-1).

[Example 70]
(2S) -2- (tert-butoxy) -2- (2- (1-cyclohexylethyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6 -Il) Acetic acid

Step 1: (2S) -Methyl 2- (tert-butoxy) -2- (2- (1-cyclohexylethyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4- Tetrahydroisoquinolin-6-yl) acetate

(S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (20 mg, 0.051 mmol) in 1,2-dichloroethane (DCE) (1 mL) was treated with 1-cyclohexylethanone (9.57 mg, 0.076 mmol) and stirred at room temperature for 15 minutes. The reaction was treated with sodium triacetoxyborohydride (16.08 mg, 0.076 mmol) and stirred at room temperature for 18 hours. The reaction was treated with additional 1-cyclohexylethanone (9.57 mg, 0.076 mmol), acetic acid (5.79 μl, 0.101 mmol), sodium triacetoxyborohydride (16.08 mg, 0.076 mmol), followed by 1.5 hours at room temperature. The mixture was stirred at 50 ° C. for 1.5 hours. The reaction was treated with titanium (IV) isopropoxide (0.059 mL, 0.202 mmol), sodium cyanoborohydride (6.36 mg, 0.101 mmol) and stirred at 50 ° C. for 5.5 hours. The reaction was cooled to room temperature overnight, diluted with saturated aqueous NaHCO3, extracted with DCM, washed with brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography (0-50% EtOAc / hexanes) gave the title compound (5.5 mg, 10.88 μmol, 21.51% yield) as a non-turbid film. LCMS (m / z) ES ⁺ = 506.5 (M + 1).

Step 2: (2S) -2- (tert-butoxy) -2- (2- (1-cyclohexylethyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydro Isoquinolin-6-yl) acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a TFA salt as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, methanol-d ₄ ) (mixture of diastereomers) δ ppm 7.37-7.21 (m, 3H), 7.13-6.98 (m, 1H), 5.12-5.02 (m, 1H), 4.58-4.27 (m, 2H), 3.94-3.76 (m, 1H), 3.47-3.23 (m, 2H), 3.18-3.04 (m, 2H), 2.43 (s, 3H), 2.38-2.28 (m, 3H), 2.00 - 1.13 (m, 17H), 1.00 - 0.82 (m, 9H); LCMS (m / z) ES + = 492.5 (M + 1), ES - = 490.5 (M-1).

[Examples 71 and 72]
(2S) -2- (tert-butoxy) -2- (5,8-dimethyl-2-((3R) -3-methylcyclohexyl) -7- (p-tolyl) -1,2,3,4- Tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from (R) -3-methylcyclohexanone in a manner similar to that described in Example 49. Isomer 1 and a mixture of both isomers were isolated as white solids as TFA salts after reverse phase HPLC.
Isomer 1: ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.36-7.20 (m, 3H), 7.13-6.97 (m, 1H), 5.13-5.01 (m, 1H), 4.40 (br. S. , 2H), 3.96-3.79 (m, 1H), 3.75-3.58 (m, 1H), 3.41-3.21 (m, 1H), 3.11 (br. S., 2H), 2.43 (s, 3H), 2.37- 2.04 (m, 5H), 2.03-1.82 (m, 5H), 1.82-1.42 (m, 5H), 1.11 (d, J = 7.1 Hz, 3H), 1.00-0.80 (m, 9H); LCMS (m / ^{z) ES + = 478.4 (M} + 1), ES - = 476.4 (M-1).
1: 1 isomeric mixture: ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 7.39-7.20 (m, 3H), 7.13-6.97 (m, 1H), 5.06 (br. S., 1H), 4.40 (br. s., 2H), 3.96-3.77 (m, 1H), 3.74-3.43 (m, 1H), 3.38-3.24 (m, 1H), 3.19-2.97 (m, 2H), 2.43 (s, 3H ), 2.37-2.08 (m, 5H), 2.06-1.83 (m, 5H), 1.82-1.44 (m, 5H), 1.16-1.03 (m, 3H), 0.99-0.83 (m, 9H); LCMS (m ^{/ z) ES + = 478.5 (} M + 1), ES - = 476.3 (M-1).

[Example 73]
(2S) -2- (tert-butoxy) -2- (5,8-dimethyl-2-((3R) -3-methylcyclopentyl) -7- (p-tolyl) -1,2,3,4- Tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from (R) -3-methylcyclopentanone in a manner similar to that described in Example 49 and isolated as a TFA salt as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, methanol-d ₄ ) (mixture of diastereomers) δ ppm 7.36-7.20 (m, 3H), 7.13-6.97 (m, 1H), 5.10-5.01 (m, 1H), 4.57-4.17 (m, 2H), 3.96-3.73 (m, 2H), 3.44-3.24 (m, 1H), 3.19-3.00 (m, 2H), 2.53-2.21 (m, 8H), 2.20-1.75 (m, 6H) , 1.52-1.27 (m, 2H), 1.18-1.05 (m, 3H), 1.01-0.80 (m, 9H); LCMS (m / z) ES ⁺ = 464.4 (M + 1).

[Example 74]
(2S) -2- (2- (Bicyclo [3.2.1] octane-3-yl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6- Yl) -2- (tert-butoxy) acetic acid

The title compound was made from bicyclo [3.2.1] octan-3-one in a manner similar to that described in Example 70, and was isolated as a TFA salt as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.38-7.20 (m, 3H), 7.15-6.97 (m, 1H), 5.06 (br. S., 1H), 4.53-4.20 (m, 2H), 4.04-3.81 (m, 1H), 3.74-3.55 (m, 1H), 3.42-3.18 (m, 1H), 3.17-2.95 (m, 2H), 2.57-2.39 (m, 5H), 2.33 (br. S ., 3H), 2.24-2.02 (m, 2H), 1.90 (s, 3H), 1.86-1.46 (m, 8H), 1.02-0.79 (m, 9H); LCMS (m / z) ES ⁺ = 490.4 ( ^{M + 1), ES - =} 488.4 (M-1).

[Example 75]
(S) -2- (tert-butoxy) -2- (2- (cycloheptanecarbonyl) -5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline-6- Yl) acetic acid

The title compound was made from cycloheptanecarboxylic acid in a manner similar to that described in Example 5 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δppm 7.37-7.19 (m, 3H), 7.13-7.01 (m, 1H), 5.06 (s, 1H), 4.73-4.51 (m, 2H), 3.92-3.75 ( m, 2H), 3.06-2.65 (m, 3H), 2.42 (s, 3H), 2.34-2.20 (m, 3H), 1.95-1.42 (m, 15H), 0.92 (s, 9H); LCMS (m / ^{z) ES + = 506.5 (M} + 1), ES - = 504.5 (M-1).

[Example 76]
(S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (1-methylcyclohexanecarbonyl) -7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline- 6-yl) acetic acid

Step 1: (S) -methyl 2- (tert-butoxy) -2- (5,8-dimethyl-2- (1-methylcyclohexanecarbonyl) -7- (p-tolyl) -1,2,3,4 -Tetrahydroisoquinolin-6-yl) acetate

(S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (20 mg, 0.051 mmol) in N, N-dimethylformamide (DMF) (1 mL) treated with 1-methylcyclohexanecarboxylic acid (10.79 mg, 0.076 mmol), DIEA (0.018 mL, 0.101 mmol), HATU (23.07 mg, 0.061 mmol). And stirred at room temperature for 2 hours. The reaction was combined with another batch of crude material (0.051 mmol scale reaction), diluted with water, extracted with EtOAc, washed with water, brine, dried over Na2SO4, filtered, concentrated and crude. (S) -Methyl 2- (tert-butoxy) -2- (5,8-dimethyl-2- (1-methylcyclohexanecarbonyl) -7- (p-tolyl) -1,2,3,4-tetrahydroisoquinoline -6-yl) acetate (72 mg, 0.139 mmol, 182% yield) was obtained as a yellow oil. LCMS (m / z) ES ⁺ = 520.5 (M + 1). The residue was used without further purification.

Step 2: (S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (1-methylcyclohexanecarbonyl) -7- (p-tolyl) -1,2,3,4- Tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made in a manner similar to that described in Step 2 of Example 4 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.37-7.20 (m, 3H), 7.07 (d, J = 7.1 Hz, 1H), 5.06 (s, 1H), 4.77-4.56 (m, 2H), 4.09-3.75 (m, 2H), 2.81 (t, J = 5.7 Hz, 2H), 2.42 (s, 3H), 2.28 (s, 3H), 2.20-2.04 (m, 2H), 1.88 (s, 3H) , 1.68 - 1.23 (m, 11H ), 0.92 (s, 9H); LCMS (m / z) ES + = 506.5 (M + 1), ES - = 504.5 (M-1).

[Example 77]
(2S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (1,2,3,4-tetrahydronaphthalen-2-yl) -7- (p-tolyl) -1, 2,3,4-Tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from beta-tetralone in a manner similar to that described in Example 49 and isolated as a white solid as a TFA salt after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.37-7.25 (m, 3H), 7.24-7.13 (m, 4H), 7.07 (br. S., 1H), 5.08 (s, 1H), 4.60- 4.44 (m, 2H), 4.06-3.81 (m, 2H), 3.57-3.41 (m, 1H), 3.40-3.24 (m, 2H), 3.20-2.93 (m, 4H), 2.57-2.39 (m, 4H ), 2.35 (s, 3H), 2.19-1.97 (m, 1H), 1.92 (s, 3H), 0.93 (br. S., 9H); LCMS (m / z) ES ⁺ = 512.5 (M + 1) ^{, ES - = 510.4 (M-} 1).

[Example 78]
(2S) -2- (tert-butoxy) -2- (5,8-dimethyl-2- (1,2,3,4-tetrahydronaphthalene-2-carbonyl) -7- (p-tolyl) -1, 2,3,4-Tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid in a manner similar to that described in Example 5 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.37-7.21 (m, 3H), 7.15-6.92 (m, 5H), 5.07 (s, 1H), 4.78-4.57 (m, 2H), 4.01-3.79 (m, 2H), 3.28-3.15 (m, 1H), 3.08-2.75 (m, 6H), 2.42 (br. s., 3H), 2.30 (s, 3H), 2.15-1.78 (m, 5H), 0.93 (s, 9H); LCMS (m / z) ES + = 540.5 (M + 1), ES - = 538.5 (M-1).

[Example 79]
(S) -2- (tert-butoxy) -2-((R) -2- (cyclohexanecarbonyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1 , 2,3,4-Tetrahydroisoquinolin-6-yl) acetic acid

Step 1: 2-nitro-N- (pent-3-yn-1-yl) benzenesulfonamide

Tert-Butyl (2-nitrophenyl) sulfonylcarbamate (21.0 g, 69.5 mmol), triphenylphosphine (21.9 g, 83.0 mmol) and penta-3-in-1-ol (6.43 g, 76.0) in THF (107 mL) To the stirred suspension of mmol) was slowly added di-tert-butyl azodicarboxylate (19.2 g, 83.0 mmol) at 0 ° C. over 15 minutes. Until the last addition, the yellow color slowly disappeared after each addition, at which point the color remained. The yellow solution was stirred at 0 ° C. for 15 minutes and then warmed to room temperature. Monitoring the reaction for an additional 3 hours by LCMS showed that the reaction had progressed to about 90% and then stopped. The solution was cooled back to 0 ° C. and an additional 2.73 g (0.15 eq) triphenylphosphine, 0.86 g (0.15 eq) penta-3-in-1-ol, then 2.40 g (0.15 eq) di- Treated with tert-butyldiazene-1,2-dicarboxylate. After stirring at 0 ° C. for 10 minutes, the solution was warmed to room temperature. After an additional 2 hours, the solution was concentrated by rotary evaporation to a syrup. Ether was added (about 300 mL) and the solution was stirred to crystallize the triphenylphosphine oxide byproduct. After stirring for 20 minutes, the solid was removed by filtration and washed twice with a small amount of ether. The filtrate was left overnight at room temperature during which time additional triphenylphosphine oxide crystallized. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was redissolved in DCM and concentrated again to give tert-butyl (2-nitrophenyl) sulfonyl (pent-3-yn-1-yl) carbamate as a pale yellow syrup (61.8 g). . This material was dissolved in DCM (150 mL) and the solution was treated with TFA (150 mL) and stirred at room temperature. Vigorous gas evolution was observed. After 1.5 hours, the solution was concentrated under reduced pressure. The residue was redissolved in 250 mL DCM and concentrated again to give a yellow oil. This material was dissolved in EtOAc (300 mL). The solution was washed with water (2 × 150 mL), brine (1 × 150 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a pale yellow oil (51.2 g). After brief stirring at room temperature, the solid began to crystallize in this material. The mixture was triturated by addition of 1: 1 ether / hexane (150 mL) to induce further crystallization. The suspension was stirred at 0 ° C. for 1 hour. The solid was collected by filtration, washed twice with 1: 1 cold ether / hexane and dried in vacuo to give the title compound (16.9 g, 91%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12-8.19 (m, 1H), 7.88-7.94 (m, 1H), 7.73-7.80 (m, 2H), 5.73 (br s, 1H), 3.22 (q, J = 6.4 Hz, 2H), 2.32-2.40 (m, 2H), 1.73 (m, 3H). LCMS (ES +) (m / z): 269.15 (M + 1).

Step 2: N- (but-2-yn-1-yl) -2-nitro-N- (pent-3-yn-1-yl) benzenesulfonamide

To a stirred MeCN solution of 2-nitro-N- (pent-3-yn-1-yl) benzenesulfonamide (16.8 g, 62.6 mmol) and 1-bromobut-2-yne (5.48 mL, 62.6 mmol) was added K. ₂ CO ₃ (17.3 g, 125 mmol) was added. The resulting mixture was stirred at room temperature. After 5 hours, the mixture was treated with an additional portion of 1-bromobut-2-yne (1.10 mL, 12.5 mmol). After an additional 2 hours, the mixture was filtered to remove solids and washed with MeCN (3 times). The filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc (250 mL). The solution was washed with diluted brine (1 ×) and saturated brine (1 ×), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a yellow syrup (22.0 g). This material was dissolved in ether (50 mL), during which time a white solid began to crystallize. The mixture was stirred and treated with hexane (75 mL) over 15 minutes. The resulting suspension was stirred for 3 days at room temperature. The solid was collected by vacuum filtration and washed with 3: 2 hexane / ether. Drying in vacuo gave the title compound (18.8 g, 94%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04-8.11 (m, 1H), 7.61-7.74 (m, 3H), 4.21 (d, J = 2.0 Hz, 2H), 3.53 (t, J = 7.3 Hz, 2H), 2.46 (m, 2H), 1.74 (m, 3H), 1.70 (s, 3H). LCMS (ES +) (m / z): 321.19 (M + 1).

Step 3: (S) -ethyl 2- (tert-butoxy) -2- (5,8-dimethyl-2-((2-nitrophenyl) sulfonyl) -7- (trimethylsilyl) -1,2,3,4 -Tetrahydroisoquinolin-6-yl) acetate and (S) -ethyl 2- (tert-butoxy) -2- (5,8-dimethyl-2-((2-nitrophenyl) sulfonyl) -6- (trimethylsilyl)- 1,2,3,4-tetrahydroisoquinolin-7-yl) acetate

A suspension of [Rh (cod) ₂ ] BF ₄ (0.950 g, 2.34 mmol) and BINAP (1.46 g, 2.34 mmol) in anhydrous DCM (75 mL) was sparged with H ₂ for 5 min and 1 atm (balloon) Stirring under H ₂ . After 1 hour, the solution was concentrated to dryness. The residue was dissolved in DCM (50 mL) and the solution was dissolved in (S) -ethyl 2- (tert-butoxy) -4- (trimethylsilyl) but-3-inoate (3.00 g, 11.7 mmol) in DCM (50 mL). Processed. The resulting solution was heated to 40 ° C. under a nitrogen atmosphere, and N- (but-2-yn-1-yl) -2-nitro-N- (pent-3-yne- Treatment with 1-yl) benzenesulfonamide (7.50 g, 23.4 mmol) in DCM (75 mL). The solution was then stirred at 40 ° C. for an additional hour and cooled to room temperature. The solution was concentrated to dryness under reduced pressure and the residue was subjected to flash chromatography (silica gel, 0-50% EtOAc / hexanes, gradient elution) to afford the title compound (4.12 g, 61%) as a white foam. Obtained as a mixture of isomers (determined by LCMS), which was subjected to the next step without separation. LCMS (ES +) (m / z): 577.46 (M + 1).

Step 4: (S) -ethyl 2- (tert-butoxy) -2- (7-iodo-5,8-dimethyl-2-((2-nitrophenyl) sulfonyl) -1,2,3,4-tetrahydro Isoquinolin-6-yl) acetate

(S) -Ethyl 2- (tert-butoxy) -2- (5,8-dimethyl-2-((2-nitrophenyl) sulfonyl) -7- (trimethylsilyl) -1,2, in MeCN (71 mL) 3,4-Tetrahydroisoquinolin-6-yl) acetate and (S) -ethyl 2- (tert-butoxy) -2- (5,8-dimethyl-2-((2-nitrophenyl) sulfonyl) -6- ( To a stirred solution of trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) acetate (4.12 g, 7.14 mmol) was added N-iodosuccinimide (1.93 g, 8.57 mmol), then TMS-Cl ( 91 μL, 0.714 mmol) was added. After stirring for 40 minutes at room temperature, the solution was partitioned between EtOAc and aqueous NaHCO ₃ and the phases were separated. The aqueous phase was extracted with an additional portion of EtOAc. The combined EtOAc solution was washed with aqueous sodium thiosulfate solution (1 time), saturated aqueous NaHCO ₃ solution (2 times), saturated brine (1 time), dried over Na ₂ SO ₄ , concentrated under reduced pressure, and pale yellow Foam (4.47 g) was obtained. The desired regioisomer (lower Rf) was isolated by flash chromatography (silica gel, 0-100% (5: 4: 1 hexane / DCM / EtOAc) / hexane, gradient elution). This gave the title compound (2.91 g, 65%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03-8.09 (m, 1H), 7.61-7.77 (m, 3H), 5.92 (s, 1H), 4.42 (s, 2H), 4.04-4.26 (m, 2H ), 3.52-3.66 (m, 2H), 2.74-2.85 (m, 2H), 2.46 (s, 3H), 2.26 (s, 3H), 1.22 (s, 12H). LCMS (ES +) (m / z) : 631.28 (M + 1).

Step 5: (S) -Ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-2-(( 2-Nitrophenyl) sulfonyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

(S) -Ethyl 2- (tert-butoxy) -2- (7-iodo-5,8-dimethyl-2-((2-nitrophenyl) sulfonyl) -1 in DMF (8 mL) in a sealed tube , 2,3,4-Tetrahydroisoquinolin-6-yl) acetate (0.500 g, 0.793 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (0.333 g, 1.59 mmol), K ₃ PO A mixture of ₄ (0.505 g, 2.38 mmol) and MePhos (58 mg, 0.159 mmol) was sparged with nitrogen for 5 minutes and treated with Pd (dba) ₂ (91 mg, 0.159 mmol). The vessel was capped and the mixture was heated to 80 ° C. with stirring. After 2 hours, the mixture was cooled to room temperature. The mixture was diluted with EtOAc and the solid was removed by filtration through celite and washed with excess EtOAc. The filtrate was washed with dilute brine (2 times) and saturated brine (1 time), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-40% EtOAc / hexanes, gradient elution) to give the title compound (0.50 g, 94%) as a tan foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02-8.09 (m, 1H), 7.68-7.76 (m, 2H), 7.61-7.67 (m, 1H), 6.63 (d, J = 11.2 Hz, 1H), 4.94 (s, 1H), 3.98-4.50 (m, 6H), 3.68-3.77 (m, 1H), 3.48-3.59 (m, 1H), 2.88 (t, J = 5.68 Hz, 2H), 2.72 (t, J = 6.4 Hz, 2H), 2.34 (s, 3H), 2.10-2.19 (m, 2H), 1.78 (s, 3H), 1.76 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H), 1.09 (s, 9H). LCMS (ES +) (m / z): 669.56 (M + 1).

Step 6: (S) -Ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1,2, 3,4-Tetrahydroisoquinolin-6-yl) acetate

(S) -Ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-2 in DMF (8 mL) To a stirred solution of-((2-nitrophenyl) sulfonyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (0.876 g, 1.31 mmol) was added Cs ₂ CO ₃ (1.71 g, 5.24 mmol). ) Followed by thiophenol (0.54 mL, 5.24 mmol). After 1 hour, the mixture was partitioned between water and EtOAc and the phases separated. The aqueous phase was extracted with an additional portion of EtOAc. The combined EtOAc solution was washed with dilute brine (2 times), saturated brine (1 time), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting yellow oil was subjected to flash chromatography (silica gel, 0-10% (2M NH _{3 in} MeOH) / DCM, gradient elution) to give the title compound (0.520 g, 82%) as a white foam. Got as. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.67 (d, J = 11.4 Hz, 1H), 4.94 (s, 1H), 4.28 (t, J = 5.0 Hz, 2H), 3.98-4.12 (m, 2H) , 3.89-3.95 (m, 2H), 3.05-3.26 (m, 2H), 2.62-2.77 (m, 4H), 2.34 (s, 3H), 2.08-2.21 (m, 2H), 1.80 (s, 3H) , 1.69 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H), 1.09 (s, 9H). LCMS (ES +) (m / z): 484.49 (M + 1).

Step 7: (S) -ethyl 2- (tert-butoxy) -2-((R) -2- (cyclohexanecarbonyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8 -Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

(S) -Ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl- in anhydrous DMF (4 mL) To a stirred solution of 1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (50 mg, 0.103 mmol), cyclohexanecarboxylic acid (20 mg, 0.155 mmol) and DIEA (54 μL, 0.310 mmol) at 0 ° C. % T3P / EtOAc (0.13 mL, 0.207 mmol) was added dropwise. After 2 hours, the solution was diluted with EtOAc. The resulting solution was washed with 10% aqueous citric acid solution / brine (twice) and saturated aqueous NaHCO ₃ solution (twice), dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure. Purification by flash chromatography (silica gel, 0-100% EtOAc / hexanes, gradient elution) gave the title compound (47 mg, 77%) as a white foam. ¹ H NMR (400 MHz, CDCl _3, mixture of rotamers) δ 6.60-6.71 (m, 1H), 4.96 (s, 1H), 3.62-4.85 (m, 8H), 2.52-2.91 (m, 5H) , 2.32-2.41 (m, 3H), 2.10-2.20 (m, 2H), 1.49-1.90 (m, 13H), 1.04-1.40 (m, 15H). LCMS (ES +) (m / z): 594.59 (M +1).

Step 8: (S) -2- (tert-butoxy) -2-((R) -2- (cyclohexanecarbonyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8- Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

(S) -Ethyl 2- (tert-butoxy) -2-((R) -2- (cyclohexanecarbonyl) -7- (8-fluoro-5-methylchroman-6) in 1,4-dioxane (3 mL) To a stirred solution of -yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (45 mg, 0.076 mmol) was obtained by adding KOTMS (49 mg, 0.379 mmol). The mixture was heated to 90 ° C. The progress of the reaction was monitored by LCMS. After 30 minutes, the temperature was raised to 100 ° C. After 1 hour, LCMS showed little or no conversion. The mixture was further treated with 30 mg of KOTMS and stirring was continued at 100 ° C. After an additional 1.5 hours, the mixture was cooled to room temperature, partitioned between DCM and 0.5 M aqueous HCl and the phases separated. The aqueous phase was extracted with DCM (2 times). The combined DCM extracts were combined and concentrated under reduced pressure. The residue was subjected to RP-HPLC purification (including _{C18,10~100% MeCN / H 2 O (} 0.1% formic acid) to give the title compound (19.5 mg, 46%) as a white solid. ¹ H NMR ( 400 MHz, CDCl _3, mixture of rotamers) δ 6.62-6.77 (m, 1H), 5.09 (br s, 1H), 4.47-4.70 (m, 2H), 4.22-4.32 (m, 2H), 3.68- 3.93 (m, 2H), 2.50-2.93 (m, 5H), 2.26 (br s, 3H), 2.07-2.18 (m, 2H), 1.46-1.93 (m, 14H), 1.22-1.41 (m, 2 H ) 1.12 (s, 9 H). LCMS (ES +) (m / z): 588.55 (M + Na).

[Example 80]
(S) -2- (tert-butoxy) -2-((R) -2- (cyclohexylsulfonyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1 , 2,3,4-Tetrahydroisoquinolin-6-yl) acetic acid

Step 1: (S) -Ethyl 2- (tert-butoxy) -2-((R) -2- (cyclohexylsulfonyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8 -Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

(S) -Ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl- in anhydrous DCM (4 mL) To a stirred solution of 1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (50 mg, 0.103 mmol) and DIEA (54 μL, 0.310 mmol) was added cyclohexanesulfonyl chloride (28.3 mg, 0.155 mmol) at 0 ° C. DCM solution was added dropwise. After 2 hours, the solution was diluted with EtOAc. The resulting solution was washed with 10% aqueous citric acid solution / brine (twice) and saturated aqueous NaHCO ₃ solution (twice), dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure. Purification by flash chromatography (silica gel, 0-50% EtOAc / hexanes, gradient elution) gave the title compound (34 mg, 52%) as a white foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.65 (d, J = 11.4 Hz, 1H), 4.96 (s, 1H), 4.22-4.49 (m, 4H), 3.96-4.15 (m, 2H), 3.51- 3.74 (m, 2H), 2.95-3.07 (m, 1H), 2.84 (t, J = 5.6 Hz, 2H), 2.72 (t, J = 6.3 Hz, 2H), 2.36 (s, 3H), 2.08-2.22 (m, 4H), 1.85-1.94 (m, 2H), 1.50-1.66 (m, 10H), 1.04-1.38 (m, 14H). LCMS (ES +) (m / z): 630.69 (M + 1).

Step 2: (S) -2- (tert-butoxy) -2-((R) -2- (cyclohexylsulfonyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8- Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was prepared according to Step 8 of Example 79 using (S) -ethyl 2- (tert-butoxy) -2-((R) -2- (cyclohexylsulfonyl) -7- (8-fluoro-5-methylchroman). Prepared in 72% yield from -6-yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.69 (d, J = 11.2 Hz, 1H), 5.10 (br s, 1H), 4.19-4.51 (m, 5H), 3.57-3.72 (m, 2H), 2.95 -3.08 (m, 1H), 2.81-2.91 (m, 2H), 2.60-2.78 (m, 2H), 2.07-2.34 (m, 6H), 1.48-1.98 (m, 12H), 1.06-1.41 (m, 11H). LCMS (ES +) (m / z): 602.50 (M + 1).

[Example 81]
(S) -2- (tert-butoxy) -2-((R) -2- (4,4-dimethylcyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8 -Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: (S) -Ethyl 2- (tert-butoxy) -2-((R) -2- (cyclohexylsulfonyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8 -Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

(S) -Ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1 in DCE (4 mL) , 2,3,4-Tetrahydroisoquinolin-6-yl) acetate (50 mg, 0.103 mmol) was added a solution of 4,4-dimethylcyclohexanone (26 mg, 0.207 mmol) in DCE (1 mL). After 15 minutes, the solution was treated with NaBH (OAc) ₃ (66 mg, 0.310 mmol) and the resulting mixture was stirred at room temperature. After 18 hours, the solution was diluted with 10% aqueous Na ₂ CO ₃ and then with DCM. The biphasic mixture was stirred vigorously for 20 minutes and the phases were separated. The aqueous solution was extracted with DCM (2 times). The combined DCM solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was subjected to flash chromatography (silica gel, 0-10% (2M NH _{3 in} MeOH) / DCM) to give the title compound (55 mg, 90%) as a white foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.66 (d, J = 11.4 Hz, 1H), 4.92 (s, 1H), 4.28 (t, J = 5.0 Hz, 2H), 3.92-4.09 (m, 2H) , 3.77 (d, J = 15.2 Hz, 1H), 3.59 (d, J = 15.2 Hz, 1H), 2.98-3.09 (m, 1H), 2.58-2.88 (m, 5H), 2.31-2.49 (m, 4H ), 2.07-2.21 (m, 2H), 1.43-1.91 (m, 12H), 1.21-1.34 (m, 2H), 1.05-1.17 (m, 12H), 0.90-0.98 (m, 6H). LCMS (ES + ) (m / z): 594.64 (M + 1).

Step 2: (S) -2- (tert-butoxy) -2-((R) -2- (4,4-dimethylcyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl)- 5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was prepared according to Step 8 of Example 79 using (S) -ethyl 2- (tert-butoxy) -2-((R) -2- (cyclohexylsulfonyl) -7- (8-fluoro-5-methylchroman). Prepared from -6-yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate as a formate in 31% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H, formate proton), 6.63 (d, J = 11.4 Hz, 1H), 4.79 (br s, 1H), 4.21-4.32 (m, 2H) , 4.00 (d, J = 15.0 Hz, 1H), 3.65 (d, J = 14.5 Hz, 1H), 3.48-3.57 (m, 1H), 2.55-3.13 (m, 5H), 2.33 (s, 3H), 2.07-2.18 (m, 2H), 1.84-2.00 (m, 2H), 1.44-1.78 (m, 9H), 1.19-1.35 (m, 2H), 1.06-1.14 (2, 9H), 0.85-0.98 (m , 6H). LCMS (ES +) (m / z): 566.57 (M + 1).

[Example 82]
(S) -2- (tert-butoxy) -2-((R) -2- (3-fluoro-2-methoxybenzoyl) -7- (8-fluoro-5-methylchroman-6-yl) -5 , 8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: (S) -ethyl 2- (tert-butoxy) -2-((R) -2- (3-fluoro-2-methoxybenzoyl) -7- (8-fluoro-5-methylchroman-6- Yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

The title compound was prepared according to Step 7 of Example 79 using (S) -ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5. , 8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate and 3-fluoro-2-methoxybenzoic acid in 81% yield. ¹ H NMR (400 MHz, CDCl ₃ , mixture of rotamers) δ 6.97-7.22 (m, 3H), 6.54-6.74 (m, 1H), 4.56-5.12 (m, 2H), 3.39-4.41 (m, 9H), 2.59-2.98 (m, 4H), 2.28-2.44 (m, 3H), 2.07-2.22 (m, 2H), 1.76-1.91 (m, 4H), 1.44-1.63 (m, 3H), 1.02- 1.33 (m, 12H). LCMS (ES +) (m / z): 636.56 (M + 1).

Step 2: (S) -2- (tert-butoxy) -2-((R) -2- (3-fluoro-2-methoxybenzoyl) -7- (8-fluoro-5-methylchroman-6-yl) ) -5,8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was prepared according to Step 8 of Example 79 using (S) -ethyl 2- (tert-butoxy) -2-((R) -2- (3-fluoro-2-methoxybenzoyl) -7- (8- Fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate was prepared in 31% yield. ¹ H NMR (400 MHz, CDCl ₃ , mixture of rotamers) δ 6.96-7.23 (m, 3H), 6.59-6.77 (m, 1H), 4.65-5.20 (m, 2H), 3.44-4.44 (m, 8H), 2.58-2.98 (m, 4H), 2.05-2.36 (m, 5H), 1.76-1.95 (m, 6H), 1.05-1.18 (m, 9H). LCMS (ES +) (m / z): 608.54 (M + 1).

[Example 83]
(2S) (M) -2- (tert-butoxy) -2-(-2- (cyclohexylsulfonyl) -5,8-dimethyl-7- (5-methylchroman-6-yl) -1,2,3 , 4-Tetrahydroisoquinolin-6-yl) acetic acid

Step 1: (S) -ethyl 2- (tert-butoxy) -2-((R) -5,8-dimethyl-7- (5-methylchroman-6-yl) -2-((2-nitrophenyl) ) Sulfonyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

(S) -Ethyl 2- (tert-butoxy) -2- (7-iodo-5,8-dimethyl-2-((2-nitrophenyl) sulfonyl)-in N, N-dimethylformamide (2.5 mL)- A degassed mixture of 1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (150 mg, 0.238 mmol) was added to 4,4,5,5-tetramethyl-2- (5-methylchroman-6- Yl) -1,3,2-dioxaborolane (130 mg, 0.476 mmol), K ₃ PO _{4 (} 152 mg, 0.714 mmol), MePhos (17.34 mg, 0.048 mmol), and finally Pd ₂ dba _{3 (} 43.6 mg, 0.048 mmol) ). The vial containing the mixture was capped and then immersed in an 80 ° C. oil bath and stirred for 150 minutes. The mixture was cooled to ambient temperature, diluted with EtOAc, washed with water, then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel (0-30% hexane / EtOAc) to give the title compound as an off-white foam (0.118 g, 76%). 1H NMR showed a 9: 1 mixture of diastereomers. LC / MS (m / z) ES ⁺ = 673 (M + 23).

Step 2: (S) -ethyl 2- (tert-butoxy) -2-((R) -5,8-dimethyl-7- (5-methylchroman-6-yl) -1,2,3,4- Tetrahydroisoquinolin-6-yl) acetate

(S) -Ethyl 2- (tert-butoxy) -2-((R) -5,8-dimethyl-7- (5-methylchroman-6-yl) in N, N-dimethylformamide (4.0 mL) A mixture of -2-((2-nitrophenyl) sulfonyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (118 mg, 0.181 mmol) and cesium carbonate (236 mg, 0.725 mmol) was added to thiophenol (0.075 mL, 0.725 mmol) and the mixture was stirred at ambient temperature until LCMS indicated that the reaction was complete (10 min). Water was added and the mixture was extracted with EtOAc. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (12 g column, 0-10% DCM / MeOH) to give a white foam (69 mg, 82%). LC / MS (m / z) ES ⁺ = 466 (M + 1).

Step 3: (S) -ethyl 2- (tert-butoxy) -2-((R) -2- (cyclohexylsulfonyl) -5,8-dimethyl-7- (5-methylchroman-6-yl) -1 , 2,3,4-Tetrahydroisoquinolin-6-yl) acetate

(S) -Ethyl 2- (tert-butoxy) -2-((R) -5,8-dimethyl-7- (5-methylchroman-6-yl) -1,2,3,4-tetrahydroisoquinoline- A solution of 6-yl) acetate (40.0 mg, 0.086 mmol) in dichloromethane (0.8 mL) is treated with DIEA (0.045 mL, 0.258 mmol), followed by cyclohexanesulfonyl chloride (0.020 mL, 0.137 mmol) and the mixture at ambient temperature. Stir overnight. The mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate and then brine. The organic phase was then dried over sodium sulfate, filtered and concentrated under reduced pressure to give a light brown residue (75 mg) that was used in the next step without further purification. LC / MS (m / z) ES ⁺ = 634 (M + 23).

Step 4: (2S) (M) -2- (tert-butoxy) -2-(-2- (cyclohexylsulfonyl) -5,8-dimethyl-7- (5-methylchroman-6-yl) -1, 2,3,4-Tetrahydroisoquinolin-6-yl) acetic acid

Crude (S) -ethyl 2- (tert-butoxy) -2-((R) -2- (cyclohexylsulfonyl) -5,8-dimethyl-7- (5-methylchroman-6-yl) -1,2 , 3,4-Tetrahydroisoquinolin-6-yl) acetate (75 mg) in 1,4-dioxane (1.0 mL) was treated with potassium trimethylsilanolate (49.0 mg, 0.344 mmol) and the flask containing the mixture was treated. Immerse in a 90 ° C. oil bath and then stir for 20 minutes. LCMS showed no reaction. Additional potassium trimethylsilanolate (49.0 mg, 0.344 mmol) was added and stirring was continued at 90 ° C. for 25 minutes. The temperature was raised to 100 ° C. and stirred for 70 minutes. Additional potassium trimethylsilanolate (49.0 mg, 0.344 mmol) was added and stirring was continued at 100 ° C. for 50 minutes. LCMS indicated that the desired product was not formed. The mixture was cooled to ambient temperature. 1N HCl was added and the mixture was extracted with EtOAc. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC to give a colorless residue. The residue was dissolved in 1,4-dioxane (0.8 mL) and then treated with 2M LiOH (0.180 mL) and the mixture was stirred in a sealed vial at 65 ° C. overnight. LCMS showed about 30% conversion to the desired product. Stirring was continued overnight at 65 ° C. LCMS showed about 40% conversion to the desired product. 2M LiOH (0.180 mL) and dioxane (0.5 mL) were further added, and the temperature was raised to 80 ° C. The mixture was stirred at 80 ° C. for 4 days and then concentrated under reduced pressure. 1N HCl was added to the resulting residue and then extracted with EtOAc. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC to give the title compound as a white solid (14 mg, 29% over 2 steps). ¹ H NMR (400MHz, chloroform-d) δ = 6.88-6.66 (m, 2H), 5.15 (m, 1H), 4.53-4.27 (m, 2H), 4.19 (t, J = 4.9 Hz, 2H), 3.78 -3.52 (m, 2H), 3.12-2.57 (m, 5H), 2.37-2.00 (m, 7H), 1.96-1.82 (m, 5H), 1.67-1.50 (m, 5H), 1.37-1.19 (m, 4H), 1.15-0.95 (m, 9H); LC / MS (m / z) ES ⁺ = 584 (M + 1).

[Example 84]
(S) (M) -2- (tert-butoxy) -2- (2-cyclohexyl-5,8-dimethyl-7- (5-methylchroman-6-yl) -1,2,3,4-tetrahydro Isoquinolin-6-yl) acetic acid

Step 1: (S) -ethyl 2- (tert-butoxy) -2-((R) -2-cyclohexyl-5,8-dimethyl-7- (5-methylchroman-6-yl) -1,2, 3,4-Tetrahydroisoquinolin-6-yl) acetate

  (2S) -Ethyl 2- (tert-butoxy) -2- (5,8-dimethyl-7- (5-methylchroman-6-yl) -1,2,3,4-tetrahydroisoquinolin-6-yl) A solution of acetate (34.0 mg, 0.073 mmol) in 1,2-dichloroethane (0.8 mL) was treated with cyclohexanone (10.59 μl, 0.102 mmol) followed by sodium triacetoxyborohydride (31.0 mg, 0.146 mmol) and the mixture Was stirred overnight at ambient temperature. The mixture is diluted with EtOAc, washed with saturated sodium bicarbonate, then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to a colorless residue (48 mg) that is further purified. Not used for next step.

Step 2: (S) (M) -2- (tert-butoxy) -2- (2-cyclohexyl-5,8-dimethyl-7- (5-methylchroman-6-yl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) acetic acid

Crude (S) -ethyl 2- (tert-butoxy) -2-((R) -2-cyclohexyl-5,8-dimethyl-7- (5-methylchroman-6-yl) -1,2,3, A solution of 4-tetrahydroisoquinolin-6-yl) acetate (48 mg) in 1,4-dioxane (1.0 mL) was treated with potassium trimethylsilanolate (41.6 mg, 0.292 mmol) and the flask containing the mixture was heated to a 90 ° C. oil. Immerse in the bath and stir for 25 minutes. LCMS showed little or no reaction. Additional potassium trimethylsilanolate (41.6 mg, 0.292 mmol) was added and stirring was continued at 90 ° C. for 20 minutes. The temperature was raised to 100 ° C. and stirred for 70 minutes. Additional potassium trimethylsilanolate (41.6 mg, 0.292 mmol) was added and stirring was continued at 100 ° C. for 50 minutes. LCMS showed little or no desired product formed. The mixture was cooled to ambient temperature. 1N HCl was added and the mixture was extracted with EtOAc. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give a colorless residue. A solution of the purified product in 1,4-dioxane (0.6 mL) and ethanol (0.2 mL) was treated with 2M LiOH (0.18 mL, 0.360 mmol) and then in a sealed vial at 90 ° C. overnight. Stir. LCMS showed> 80% conversion to the desired product. Stirring was continued overnight at 90 ° C. The mixture was concentrated. 1N HCl was added to the resulting residue and then extracted with EtOAc. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC to give the title compound as a pale yellow solid (6 mg). ¹ H NMR (400MHz, chloroform-d) δ = 6.78 (d, J = 8.2 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 4.79 (br. S., 1H), 4.25-4.12 ( m, 2H), 3.83 (d, J = 14.7 Hz, 1H), 3.59-3.33 (m, 1H), 3.13-2.97 (m, 1H), 2.85-2.56 (m, 5H), 2.39-2.27 (m, 3H), 2.18-1.97 (m, 4H), 1.91-1.65 (m, 4H), 1.63-1.50 (m, 5H), 1.47-1.23 (m, 5H), 1.20-1.04 (m, 10H); LC / MS (m / z) ES ⁺ = 520 (M + 1).

[Example 85]
(S) -2- (tert-butoxy) -2-((R) -2- (cyclohexylmethyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1 , 2,3,4-Tetrahydroisoquinolin-6-yl) acetic acid

Step 1: (S) -ethyl 2- (tert-butoxy) -2-((R) -2- (cyclohexylmethyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8 -Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

The title compound was prepared according to Step 1 of Example 81 using (S) -ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5. , 8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate and cyclohexanecarbaldehyde were prepared in 88% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.66 (d, J = 11.5 Hz, 1H), 4.92 (s, 1H), 4.28 (t, J = 4.9 Hz, 2H), 3.92-4.12 (m, 2H) , 3.57 (d, J = 15.4 Hz, 1H), 3.45 (d, J = 6.4 Hz, 1H), 3.36 (d, J = 15.4 Hz, 1H), 2.62-2.90 (m, 4H), 2.47-2.59 ( m, 1H), 2.28-2.40 (m, 5H), 2.06-2.21 (m, 2H), 1.51-1.95 (m, 13H), 0.84-1.39 (m, 16H). LCMS (ES +) (m / z) : 580.61 (M + 1).

Step 2: (S) -2- (tert-butoxy) -2-((R) -2- (cyclohexylmethyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8- Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

(S) -Ethyl 2- (tert-butoxy) -2-((R) -2- (cyclohexylmethyl) -7- (8-fluoro-) in 2: 1 dioxane / EtOH (3 mL) in a glass pressure vessel To a stirred solution of 5-methylchroman-6-yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (52 mg, 0.090 mmol) was added 2M aqueous LiOH (0.89 mL). 1.79 mmol). The reaction vessel was sealed and the mixture was heated to 80 ° C. After 1 hour, LCMS showed only a few percent conversion and a significant amount of solid remained suspended in the reaction mixture. The mixture was treated with 0.5 mL water to dissolve most of the solid. The resulting mixture was heated at 85 ° C. for 18 hours, at which time LCMS indicated that the reaction was complete. The mixture was cooled to room temperature, diluted with DCM and poured into rapidly stirred 1M aqueous HCl (25 mL). The pH was adjusted to about 6.0 by adding 1 M aqueous NaOH and the phases were separated. The aqueous phase was extracted with DCM (2 times). The combined DCM solution was dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure. The residue was subjected to RP-HPLC purification (C18, 10-100% MeCN / H ₂ O with 0.1% formic acid) to give the title compound (28.4 mg, 53%) as a formate salt as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H, formate proton), 6.63 (d, J = 11.4 Hz, 1H), 4.85 (br s, 1H), 4.26 (t, J = 4.8 Hz , 2H), 3.99 (d, J = 15.6 Hz, 1H), 3.38-3.58 (m, 3H), 2.57-3.11 (m, 6H), 2.30-2.36 (s, 3H), 2.07-2.17 (m, 2H ), 1.54-1.93 (m, 13H), 0.89-1.36 (m, 13H). LCMS (ES +) (m / z): 552.48 (M + 1).

[Example 86]
(S) -2- (tert-butoxy) -2- (7- (4-chlorophenyl) -2- (cyclohexylsulfonyl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl Acetic acid

The title compound was prepared from (4-chlorophenyl) boronic acid in a manner similar to that described in Steps 1-6 of Example 79 and Steps 3-4 of Example 83, and after reverse phase HPLC, Isolated as a white solid. ¹ H NMR (400MHz, methanol-d ₄ ) δ = 7.52-7.37 (m, 1H), 7.24-7.16 (m, 1H), 4.97 (s, 1H), 4.51-4.34 (m, 2H), 3.73-3.54 (m, 2H), 3.24-3.13 (m, 1H), 2.89-2.80 (m, 2H), 2.30 (s, 3H), 2.13 (d, J = 11.5 Hz, 2H), 1.94-1.81 (m, 5H ), 1.75-1.66 (m, 1H), 1.59-1.46 (m, 2H), 1.43-1.14 (m, 3H), 0.95 (s, 9H); LC / MS (m / z) ES ⁺ = 571 (M +23).

[Example 87]
(S) -2- (tert-Butoxy) -2- (7- (4-Chlorophenyl) -2-cyclohexyl-5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was prepared in a similar manner as described in Example 84 and isolated as a tan solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ = 7.66-7.60 (m, 1H), 7.47-7.40 (m, 2H), 7.17-7.12 (m, 1H), 4.80 (s, 1H), 4.26 (s , 2H), 3.48 (br. S., 2H), 3.15-2.91 (m, 2H), 2.40-2.30 (m, 3H), 2.24-2.13 (m, 2H), 2.04-1.94 (m, 2H), 1.90-1.81 (m, 3H), 1.80-1.70 (m, 1H), 1.68-1.55 (m, 2H), 1.52-1.37 (m, 2H), 1.35-1.20 (m, 2H), 0.89 (s, 9H ); LC / MS (m / z) ES ⁺ = 484 (M + 1).

[Example 88]
(S) (M) -2- (tert-butoxy) -2- (7- (8-chloro-5-methylchroman-6-yl) -2- (cyclohexylsulfonyl) -5,8-dimethyl-1, 2,3,4-Tetrahydroisoquinolin-6-yl) acetic acid

The title compound is prepared in a manner similar to that described in Steps 1-6 of Example 79 and Steps 3-4 of Example 83 in 2- (8-chloro-5-methylchroman-6-yl) Prepared from -4,4,5,5-tetramethyl-1,3,2-dioxaborolane and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 6.86 (s, 1H), 4.97 (s, 1H), 4.42 (s, 2H), 4.26 (t, J = 5.0 Hz, 2H), 3.65 (t, J = 5.9 Hz, 2H), 3.23-3.12 (m, 1H), 2.84 (t, J = 5.7 Hz, 2H), 2.74 (t, J = 6.4 Hz, 2H), 2.35 (s, 3H), 2.17- 2.05 (m, 4H), 1.92-1.81 (m, 5H), 1.76 (s, 3H), 1.74-1.66 (m, 1H), 1.59-1.45 (m, 2H), 1.42-1.17 (m, 3H), 1.08 (s, 9H); LC / MS (m / z) ES ⁺ = 641 (M + 23).

[Example 89]
(S) (M) -2- (tert-butoxy) -2- (7- (8-chloro-5-methylchroman-6-yl) -2-cyclohexyl-5,8-dimethyl-1,2,3 , 4-Tetrahydroisoquinolin-6-yl) acetic acid

The title compound was prepared in a similar manner as described in Example 84 and isolated as a tan solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ = 6.82 (s, 1H), 4.79 (s, 1H), 4.24 (t, J = 5.0 Hz, 2H), 4.20-4.08 (m, 2H), 3.55- 3.44 (m, 1H), 3.34-3.16 (m, 2H), 3.15-2.88 (m, 2H), 2.83-2.62 (m, 2H), 2.40 (s, 3H), 2.24-2.03 (m, 4H), 2.00-1.90 (m, 2H), 1.83-1.68 (m, 7H), 1.66-1.52 (m, 2H), 1.49-1.34 (m, 2H), 1.32-1.21 (m, 1H), 1.06 (s, 9H ); LC / MS (m / z) ES ⁺ = 554 (M + 1).

[Example 90]
(S) -2-((R) -2-Benzyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-6 -Yl) -2- (tert-butoxy) acetic acid

Step 1: (2S) -Ethyl 2- (2-benzyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-6 -Yl) -2- (tert-butoxy) acetate

The title compound was prepared according to Step 1 of Example 81 using (S) -ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5. , 8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate and benzaldehyde were prepared in 89% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24-7.46 (m, 5H), 6.65 (d, J = 11.4 Hz, 1H), 4.93 (s, 1H), 4.28 (t, J = 5.1 Hz, 2H) , 3.92-4.12 (m, 2H), 3.41-3.82 (m, 4H), 2.52-2.93 (m, 6H), 2.33 (s, 3H), 2.08-2.19 (m, 2H), 1.79 (s, 3H) , 1.67 (s, 3H), 1.05-1.18 (m, 12H). LCMS (ES +) (m / z): 574.51 (M + 1).

Step 2: (S) -2-((R) -2-benzyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1,2,3,4-tetrahydro Isoquinolin-6-yl) -2- (tert-butoxy) acetic acid

The title compound was prepared according to Step 2 of Example 85 with (2S) -ethyl 2- (2-benzyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1,2 , 3,4-tetrahydroisoquinolin-6-yl) -2- (tert-butoxy) acetate was prepared in 54% yield. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.22-7.45 (m, 5H), 6.61 (d, J = 11.4 Hz, 1H), 4.83 (br s, 1H), 4.19-4.36 (m, 2H), 3.97 (d, J = 12.6 Hz, 1H), 3.67-3.83 (m, 2H), 3.26-3.48 (m, 1H), 2.41-3.00 (m, 6H), 2.29 (s, 3H), 2.03-2.19 (m , 2 H), 1.49 (s, 3H), 1.36 (br s, 3H), 1.07-1.19 (m, 9H). LCMS (ES +) (m / z): 546.49 (M + 1).

[Example 91]
(S) -2-((R) -2-Benzoyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-6 -Yl) -2- (tert-butoxy) acetic acid

Step 1: (S) -Ethyl 2-((R) -2-benzoyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1,2,3,4- Tetrahydroisoquinolin-6-yl) -2- (tert-butoxy) acetate

The title compound was prepared according to Step 1 of Example 80 according to (S) -ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5. , 8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate and benzoyl chloride were prepared in 92% yield. ¹ H NMR (400 MHz, CDCl ₃ , mixture of rotamers) δ 7.36-7.56 (m, 5H), 6.58-6.75 (m, 1H), 4.58-5.03 (m, 2H), 4.23-4.34 (m, 2H), 3.96-4.18 (m, 2H), 3.49-3.84 (m, 1H), 2.61-2.96 (m, 5H), 2.38 (s, 3H), 2.08-2.21 (m, 2H), 1.41-1.96 ( m, 7H), 1.05-1.21 (m, 12 H). LCMS (ES +) (m / z): 588.53 (M + 1).

Step 2: (S) -2-((R) -2-benzoyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1,2,3,4-tetrahydro Isoquinolin-6-yl) -2- (tert-butoxy) acetic acid

The title compound was prepared according to Step 8 of Example 79 using (S) -ethyl 2-((R) -2-benzoyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl. Prepared from -1,2,3,4-tetrahydroisoquinolin-6-yl) -2- (tert-butoxy) acetate in 41% yield. ¹ H NMR (400 MHz, CDCl ₃ , mixture of rotamers) δ 7.39-7.54 (m, 5H), 6.63-6.76 (m 1H), 5.10 (br s, 1H), 4.80 (br s, 1H), 4.22-4.32 (m, 3H), 3.68 (br s, 1H), 3.49 (br s, 1H), 2.58-2.97 (m, 4H), 2.27 (br s, 3H), 2.07-2.18 (m, 2 H ) 1.86 (br s, 6H), 1.13 (s, 9H). LCMS (ES +) (m / z): 560.44 (M + 1).

[Example 92]
(S) -2- (tert-butoxy) -2-((R) -2- (3-fluoro-4-methoxybenzoyl) -7- (8-fluoro-5-methylchroman-6-yl) -5 , 8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: (S) -ethyl 2- (tert-butoxy) -2-((R) -2- (3-fluoro-4-methoxybenzoyl) -7- (8-fluoro-5-methylchroman-6- Yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

The title compound was prepared according to Step 7 of Example 79 using (S) -ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5. , 8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate and 3-fluoro-4-methoxybenzoic acid were prepared in quantitative yield. ¹ H NMR (400 MHz, CDCl ₃ , mixture of rotamers) δ 7.20-7.32 (m, 2H), 7.01 (t, J = 8.0 Hz, 1H), 6.65 (d, J = 11.2 Hz, 1H), 4.97 (br s, 1H), 4.51-5.01 (m, 3H), 4.28 (t, J = 4.7 Hz, 2H), 3.51-4.18 (m, 6H), 2.61-2.97 (m, 4H), 2.38 (s , 3H), 2.09-2.21 (m, 2H), 1.52-1.94 (m, 6H), 1.03-1.21 (m, 12H). LCMS (ES +) (m / z): 636.48 (M + 1).

Step 2: (S) -2- (tert-butoxy) -2-((R) -2- (3-fluoro-4-methoxybenzoyl) -7- (8-fluoro-5-methylchroman-6-yl) ) -5,8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was prepared according to Step 8 of Example 79 using (S) -ethyl 2- (tert-butoxy) -2-((R) -2- (3-fluoro-4-methoxybenzoyl) -7- (8- Fluoro-5-methylchroman-6-yl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate was prepared in 24% yield. ¹ H NMR (400 MHz, CDCl ₃ , mixture of rotamers) δ 7.22-7.33 (m, 2H), 7.02 (t, J = 8.2 Hz, 1H), 6.69 (d, J = 10.8 Hz, 1H), 4.67-5.18 (m, 1H), 4.27 (t, J = 4.9 Hz, 2H), 3.58-4.05 (m, 8H), 1.72-2.96 (m, 14H), 1.13 (s, 9H). LCMS (ES +) (m / z): 608.51 (M + 1).

[Example 93]
(S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -2- (3-isopropoxybenzoyl) -5,8- Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: (S) -Ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -2- (3-isopropoxybenzoyl)- 5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

The title compound was prepared according to Step 7 of Example 79 using (S) -ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5. , 8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate and 3-isopropoxybenzoic acid were prepared in 98% yield. ¹ H NMR (400 MHz, CDCl ₃ , mixture of rotamers) δ 7.26-7.40 (m, 1H), 6.90-7.07 (m, 3H), 6.58-6.74 (m, 1H), 3.52-5.04 (m, 10H), 2.59-3.00 (m, 4H), 2.37 (s, 3H), 2.09-2.21 (m, 2H), 1.68-1.93 (m, 6H) 1.01-1.44 (m, 18H). LCMS (ES +) ( m / z): 646.57 (M + 1).

Step 2: (S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -2- (3-isopropoxybenzoyl) -5 , 8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was prepared according to Step 8 of Example 79 according to (S) -ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -2. Prepared in 24% yield from-(3-isopropoxybenzoyl) -5,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate. ¹ H NMR (400 MHz, CDCl ₃ , mixture of rotamers) δ 7.25-7.40 (m, 1H), 6.91-7.07 (m, 3H), 6.63-6.76 (m, 1H), 3.60-5.18 (m, 8H), 2.58-2.98 (m, 4H), 2.27 (br s, 3H), 2.06-2.18 (m, 2H) 0.97-1.95 (m, 21 H). LCMS (ES +) (m / z): 618.55 ( M + 1).

[Example 94]
(S) -2- (tert-Butoxy) -2-((R) -7- (8-Fluoro-5-methylchroman-6-yl) -5,8-dimethyl-2- (4- (trifluoro) Methyl) benzoyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: (S) -Ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-2- (4 -(Trifluoromethyl) benzoyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

The title compound was prepared according to Step 7 of Example 79 using (S) -ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5. , 8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate and 4- (trifluoromethyl) benzoic acid in 98% yield. ¹ H NMR (400 MHz, CDCl ₃ , mixture of rotamers) δ 7.54-7.84 (m, 4H), 6.59-6.76 (m, 1H), 3.90-5.19 (m, 9H), 3.49-3.79 (m, 1H), 2.59-3.02 (m, 4H), 0.89-2.46 (m, 22H). LCMS (ES +) (m / z): 656.50 (M + 1).

Step 2: (S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-2- (4- (Trifluoromethyl) benzoyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was prepared according to Step 8 of Example 79 using (S) -ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5. , 8-dimethyl-2- (4- (trifluoromethyl) benzoyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate was prepared in 11% yield. ¹ H NMR (400 MHz, CDCl ₃ , mixture of rotamers) δ 7.53-7.81 (m, 4H), 6.60-6.77 (m, 1H), 3.53-5.18 (m, 7H), 2.59-2.99 (m, 5H), 2.04-2.34 (m, 5H), 1.87 (br s, 6H), 1.13 (s, 9H). LCMS (ES +) (m / z): 628.50 (M + 1).

[Example 95]
(S) (M) -2- (tert-butoxy) -2- (2- (cyclohexylsulfonyl) -5,8-dimethyl-7- (5-methyl-3,4-dihydro-2H-benzo [b] [1,4] Oxazin-6-yl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was prepared in a manner similar to that described in Steps 1-6 of Example 79 and Steps 3-4 of Example 83, using 5-methyl-6- (4,4,5,5-tetra Prepared from methyl-1,3,2-dioxaborolan-2-yl) -3,4-dihydro-2H-benzo [b] [1,4] oxazine and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ = 6.63 (d, J = 8.1 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H), 5.08 (s, 1H), 4.42 (s, 2H) , 4.22 (t, J = 4.1 Hz, 2H), 3.65 (t, J = 5.9 Hz, 2H), 3.46 (d, J = 3.8 Hz, 2H), 3.22-3.11 (m, 1H), 2.84 (t, J = 5.8 Hz, 2H), 2.33 (s, 3H), 2.12 (d, J = 11.4 Hz, 2H), 1.86 (d, J = 12.8 Hz, 2H), 1.78-1.65 (m, 7H), 1.52 ( dq, J = 2.7, 12.3 Hz, 2H), 1.41-1.15 (m, 4H), 1.07 (s, 9H); LC / MS (m / z) ES ⁺ = 585 (M + 1).

[Example 96]
(S) -2- (tert-Butoxy) -2-((R) -7- (8-Fluoro-5-methylchroman-6-yl) -5,8-dimethyl-2- (6-methylnicotinoyl) ) -1,2,3,4-Tetrahydroisoquinolin-6-yl) acetic acid

Step 1: (S) -ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-2- (6 -Methylnicotinoyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

The title compound was prepared according to Step 7 of Example 79 using (S) -ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5. , 8-dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate and 6-methylnicotinic acid in 98% yield. ¹ H NMR (400 MHz, CDCl ₃ , mixture of rotamers) δ 8.65 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.17-7.32 (m, 1H), 6.56-6.73 (m , 1H), 3.49-5.05 (m, 9H), 2.53-2.98 (m, 7H), 2.37 (s, 3H), 2.09-2.21 (m, 2H), 1.47-1.96 (m, 6H), 1.02-1.22 (m, 12 H). LCMS (ES +) (m / z): 603.50 (M + 1).

Step 2: (S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-2- (6- Methylnicotinoyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was prepared according to Step 8 of Example 79 using (S) -ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5. , 8-dimethyl-2- (6-methylnicotinoyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate was prepared in 20% yield. ¹ H NMR (400 MHz, CDCl ₃ , mixture of rotamers) δ 8.66 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.20-7.32 (m, 1H), 6.59-6.79 (m , 1H), 3.57-5.19 (m, 7H), 2.52-2.99 (m, 7H), 2.29 (s, 3H), 2.05-2.19 (m, 2H), 1.85 (br s, 6H), 1.13 (s, 9H). LCMS (ES +) (m / z): 575.45 (M + 1).

[Example 97]
(S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -2- (4-methoxy-3-methylbenzoyl) -5 , 8-Dimethyl-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

The title compound was made from 4-methoxy-3-methylbenzoic acid in a manner similar to that described in Example 5 and isolated as a white solid after reverse phase HPLC. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.42-7.18 (m, 2H), 7.00 (d, J = 7.5 Hz, 1H), 6.60 (d, J = 10.4 Hz, 1H), 5.00 (br. s., 1H), 4.79-4.51 (m, 2H), 4.23 (br. s., 2H), 4.06-3.64 (m, 5H), 2.87 (br. s., 2H), 2.73 (br. s. , 2H), 2.37 (s, 3H), 2.23 (br. S., 3H), 2.12 (br. S., 2H), 1.95-1.46 (m, 6H), 1.09 (s, 9H); LCMS (m ^{/ z) ES + = 604.4 (} M + 1), ES - = 602.4 (M-1).

[Example 98]
2- (2-Benzyl-5,8-dimethyl-3-oxo-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2- (tert-butoxy) acetic acid

Step 1: N-benzyl-N- (but-2-yn-1-yl) pent-3-inamide

To a mixture of N-benzylbut-2-in-1-amine (1.43 g, 8.99 mmol), penta-3-ynoic acid (800 mg, 8.16 mmol) in THF (15 mL), EDCI (2.33 g, 12.24 mmol) and TEA (1.65 g, 16.32 mmol) was added. After stirring at room temperature for 1.5 hours, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-10% EtOAc in PE). The title compound (1.1 g, 56% yield) was obtained as a colorless oil. LC-MS (ESI): m / z (M + 1) = 240.42.

Step 2: Ethyl (S) -2- (2-benzyl-5,8-dimethyl-3-oxo-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2 -Hydroxyacetate

A mixture of Rh (cod) ₂ BF ₄ (10 mg, 0.023 mmol) and BINAP (15 mg, 0.023 mmol) in DCM (1 mL) was stirred at room temperature for 5 hours under H ₂ atmosphere. After concentration, the resulting mixture was dissolved in DCM (1 mL) and ethyl 2-hydroxy-4- (p-tolyl) but-3-inoate (50 mg, 0.229 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 40 ° C. and N-benzyl-N- (but-2-yn-1-yl) pent-3-inamide (109 mg, 0.458 mmol) was added as a DCM solution (1 mL) 30 Added over a minute. After stirring at 40 ° C. for 30 minutes, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (16 mg, 15% yield) was obtained. LC-MS (ESI): m / z (M + 1) = 458.09.

Step 3: Ethyl 2- (2-benzyl-5,8-dimethyl-3-oxo-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2- (tert- Butoxy) acetate

Ethyl (S) -2- (2-benzyl-5,8-dimethyl-3-oxo-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2-hydroxyacetate To a solution of (16 mg, 0.035 mmol) in t-BuOAc (1.75 mL) was added HClO ₄ (5 mg, 0.035 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) The title compound (9 mg, 50% yield) was obtained. LC-MS (ESI): m / z (M + 1) = 514.12.

Step 4: 2- (2-Benzyl-5,8-dimethyl-3-oxo-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2- (tert-butoxy Acetic acid

Ethyl 2- (2-benzyl-5,8-dimethyl-3-oxo-7- (p-tolyl) -1,2,3,4-tetrahydro in dioxane (1.0 mL) and H ₂ O (0.2 mL) To a mixture of isoquinolin-6-yl) -2- (tert-butoxy) acetate (9 mg, 0.018 mmol) was added LiOH (7 mg, 0.18 mmol). After stirring at 80 ° C. for 4 hours, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, 0 to 100% MeCN in H ₂ O containing this HPLC (C18,0.1% formic acid ) To give the title compound (2.3 mg, 27% yield). LC-MS (ESI): m / z (M + 1) = 486.11. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.68 (br, 1H), 7.38-7.27 (m, 5H), 7.26-7.18 (m , 3H), 7.01 (d, J = 8.4 Hz, 1H), 5.14 (s, 1H), 4.88-4.73 (m, 2H), 4.35 (s, 2H), 3.69 (q, J = 20.3 Hz, 2H) , 2.40 (s, 3H), 2.25 (s, 3H), 1.76 (s, 3H), 0.97 (s, 9H).

[Example 99]
2- (2-Benzyl-5,8-dimethyl-3-oxo-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert-butoxy) acetic acid

Step 1: Ethyl (S) -2- (2-benzyl-5,8-dimethyl-3-oxo-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2 -Hydroxyacetate

A mixture of Rh (cod) ₂ BF ₄ (10 mg, 0.023 mmol) and BINAP (15 mg, 0.023 mmol) in DCM (1 mL) was stirred at room temperature for 5 hours under H ₂ atmosphere. After concentration, the resulting mixture was dissolved in DCM (1 mL) and ethyl 2-hydroxy-4- (p-tolyl) but-3-inoate (50 mg, 0.229 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 40 ° C. and N-benzyl-N- (but-2-yn-1-yl) pent-3-inamide (109 mg, 0.458 mmol) was added as a DCM solution (1 mL) 30 Added over a minute. After stirring at 40 ° C. for 30 minutes, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (20 mg, 19% yield) was obtained. LC-MS (ESI): m / z (M + 1) = 458.09.

Step 2: Ethyl 2- (2-benzyl-5,8-dimethyl-3-oxo-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert- Butoxy) acetate

Ethyl (S) -2- (2-benzyl-5,8-dimethyl-3-oxo-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2-hydroxyacetate To a solution of (20 mg, 0.043 mmol) in t-BuOAc (2 mL) was added HClO ₄ (6.2 mg, 0.043 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (17 mg, 77% yield). LC-MS (ESI): m / z (M + 1) = 514.09.

Step 3: 2- (2-Benzyl-5,8-dimethyl-3-oxo-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert-butoxy Acetic acid

Ethyl 2- (2-benzyl-5,8-dimethyl-3-oxo-6- (p-tolyl) -1,2,3,4-tetrahydro in dioxane (1.0 mL) and H ₂ O (0.2 mL) To a mixture of isoquinolin-7-yl) -2- (tert-butoxy) acetate (17 mg, 0.033 mmol) was added LiOH (15.8 mg, 0.662 mmol). After stirring at 80 ° C. for 4 hours, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product which purified by HPLC (0 to 100% MeCN in H ₂ O containing C18,0.1% formic acid) To give the title compound (6.8 mg, 42% yield). LC-MS (ESI): m / z (M + 1) = 486.39. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.68 (br, 1H), 7.37-7.28 (m, 5H), 7.26-7.20 (m , 3H), 7.05 (d, J = 7.3 Hz, 1H), 5.15 (s, 1H), 4.82 (dd, J = 54.3, 14.8 Hz, 2H), 4.38 (s, 2H), 3.76-3.58 (m, 2H), 2.41 (s, 3H), 2.09 (s, 3H), 1.91 (s, 3H), 0.95 (s, 9H).

[Example 100]
(S) -2- (2-Benzyl-5,8-dimethyl-3-oxo-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert- Butoxy) acetic acid

Step 1: (S) -ethyl 2- (2-benzyl-5,8-dimethyl-3-oxo-6- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2-hydroxy acetate

A solution of BINAP (62.2 mg, 0.100 mmol) and bis (1,5-cyclooctadiene) rhodium (I) tetrafluoroborate (40.5 mg, 0.100 mmol) in dichloromethane (5 mL) was stirred at ambient temperature for 5 minutes. The mixture was purged with hydrogen gas for 1 minute and then stirred under a balloon of hydrogen for 1 hour. The mixture was concentrated. A solution of (S) -ethyl 2-hydroxy-4- (trimethylsilyl) but-3-inoate (100 mg, 0.499 mmol) in dichloromethane (3 mL) was added. The mixture was heated to 40 ° C. and N-benzyl-N- (but-2-yn-1-yl) pent-3-inamide (358 mg, 1.498 mmol) in dichloromethane (3 mL) was added to the mixture over 2 h. Slowly added. The mixture was stirred at 40 ° C. for 18 hours and then left to stand at ambient temperature over the weekend. LCMS / TLC showed that a mixture of regioisomers had formed. The mixture was concentrated and then purified on silica gel (0-50% hexane / EtOAc gradient elution, early eluting regioisomer) to give the title compound as a pale yellow residue (84 mg, 38% ). ¹ H NMR (400MHz, chloroform-d) δ = 7.38-7.22 (m, 5H), 5.55 (s, 1H), 4.86-4.71 (m, 2H), 4.37-4.23 (m, 3H), 4.20-4.09 ( m, 1H), 3.64 (s, 2H), 3.31 (br.s., 1H), 2.37 (s, 3H), 1.99 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H), 0.46 ( s, 9H); LC / MS (m / z) ES ⁺ = 440 (M + 1).

Step 2: (S) -ethyl 2- (2-benzyl-6-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-hydroxyacetate

(S) -Ethyl 2- (2-benzyl-5,8-dimethyl-3-oxo-6- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2-hydroxyacetate (84 mg , 0.191 mmol) in ice cold dichloromethane (1.0 mL) was slowly treated with ICI (1M solution in dichloromethane) (0.210 mL, 0.210 mmol) and the mixture was stirred at ice bath temperature for 10 min. The mixture was quenched with saturated sodium thiosulfate and then extracted with dichloromethane. The extract was washed with saturated sodium bicarbonate, then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow residue (102 mg, quantitative). LC / MS (m / z) ES ⁺ = 494 (M + 1).

Step 3: (S) -Ethyl 2- (2-benzyl-6-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert- Butoxy) acetate

(S) -Ethyl 2- (2-benzyl-6-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl in t-butyl acetate (3.0 mL) The suspension of) -2-hydroxyacetate was treated with perchloric acid (0.046 mL, 0.764 mmol) and the pale yellow solution was stirred at ambient temperature for 45 minutes. The mixture was partitioned between EtOAc and 1N NaOH. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g column, 0-50% hexane / EtOAc) to give a pale yellow foam (57 mg, 50%). ¹ H NMR (400MHz, chloroform-d) δ = 7.38-7.28 (m, 5H), 5.92 (s, 1H), 4.79 (s, 2H), 4.30 (s, 2H), 4.23-4.04 (m, 2H) , 3.72 (s, 2H), 2.52 (s, 3H), 2.16 (s, 3H), 1.24-1.15 (m, 12H); LC / MS (m / z) ES ⁺ = 550 (M + 1).

Step 4: (S) -ethyl 2- (2-benzyl-5,8-dimethyl-3-oxo-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2 -(tert-Butoxy) acetate

(S) -Ethyl 2- (2-benzyl-6-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-7 in N, N-dimethylformamide (1.0 mL) -Yl) -2- (tert-butoxy) acetate (20.50 mg, 0.037 mmol) was added to p-tolylboronic acid (10.15 mg, 0.075 mmol), K ₃ PO ₄ (23.76 mg, 0.112 mmol), MePhos (2.72 mg, 7.46 μmol) and finally Pd ₂ dba ₃ (6.83 mg, 7.46 μmol) was added to degas. The mixture was degassed for several minutes and then stirred at 80 ° C. overnight. The mixture was cooled to ambient temperature and diluted with EtOAc, washed with water, then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give a pale yellow residue (7.4 mg, 39%). ¹ H NMR (400MHz, chloroform-d) δ = 7.39-7.28 (m, 5H), 7.25-7.16 (m, 3H), 7.06-7.01 (m, 1H), 4.98 (s, 1H), 4.82 (s, 2H), 4.39 (s, 2H), 4.22-3.98 (m, 2H), 3.67 (s, 2H), 2.43 (s, 3H), 2.19 (s, 3H), 1.88 (s, 3H), 1.21 (t , J = 7.1 Hz, 3H), 0.94 (s, 9H); LC / MS (m / z) ES ⁺ = 514 (M + 1).

Step 5: (S) -2- (2-benzyl-5,8-dimethyl-3-oxo-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert-Butoxy) acetic acid

(S) -Ethyl 2- (2-benzyl-5,8-dimethyl-3-oxo-6- (p-tolyl) -1,2,3,4 in tetrahydrofuran (0.6 mL) and ethanol (0.3 mL) A mixture of -tetrahydroisoquinolin-7-yl) -2- (tert-butoxy) acetate (7.4 mg, 0.014 mmol) was treated with 2M LiOH (0.3 mL, 0.600 mmol). The mixture was heated to 70 ° C. and stirred for 8 hours. The mixture was then stirred overnight at ambient temperature. The mixture was concentrated, diluted with 1N HCl and then extracted with EtOAc. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to a pale yellow residue. The residue was purified by reverse phase HPLC to give the title compound as a white solid (3.2 mg, 47%). ¹ H NMR (400MHz, chloroform-d) δ = 7.40-7.20 (m, 8H), 7.10-7.01 (m, 1H), 5.16 (s, 1H), 4.93-4.85 (m, 1H), 4.79-4.71 ( m, 1H), 4.39 (s, 2H), 3.78-3.56 (m, 2H), 2.42 (s, 3H), 2.09 (s, 3H), 1.92 (s, 3H), 0.96 (s, 9H); LC / MS (m / z) ES ⁺ = 486 (M + 1).

[Example 101]
(S) -2- (2-Benzyl-5,8-dimethyl-3-oxo-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2- (tert- Butoxy) acetic acid

Step 1: (S) -ethyl 2- (2-benzyl-5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2-hydroxy acetate

A solution of BINAP (62.2 mg, 0.100 mmol) and bis (1,5-cyclooctadiene) rhodium (I) tetrafluoroborate (40.5 mg, 0.100 mmol) in dichloromethane (5 mL) was stirred at ambient temperature for 5 minutes. The mixture was purged with hydrogen gas for 1 minute and then stirred under a balloon of hydrogen for 1 hour. The mixture was concentrated. A solution of (S) -ethyl 2-hydroxy-4- (trimethylsilyl) but-3-inoate (100 mg, 0.499 mmol) in dichloromethane (3 mL) was added. The mixture was heated to 40 ° C. and N-benzyl-N- (but-2-yn-1-yl) pent-3-inamide (358 mg, 1.498 mmol) in dichloromethane (3 mL) was added to the mixture over 2 h. Slowly added. The mixture was stirred at 40 ° C. for 18 hours and then left to stand at ambient temperature over the weekend. LCMS / TLC showed that a mixture of regioisomers had formed. The mixture was concentrated and then purified on silica gel (gradient elution from 0 to 50% hexane / EtOAc, later eluting regioisomer) to give the title compound as a pale yellow residue (81 mg, 37%). Obtained. ¹ H NMR (400MHz, chloroform-d) δ = 7.38-7.27 (m, 5H), 5.54 (s, 1H), 4.80 (s, 2H), 4.40-4.26 (m, 3H), 4.24-4.09 (m, 1H), 3.63 (s, 2H), 3.35 (s, 1H), 2.21 (s, 3H), 2.14 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H), 0.44 (s, 9H); LC / MS (m / z) ES ⁺ = 440 (M + 1).

Step 2: (S) -Ethyl 2- (2-benzyl-7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) -2-hydroxyacetate

(S) -Ethyl 2- (2-benzyl-5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2-hydroxyacetate (81 mg , 0.184 mmol) in ice cold dichloromethane (1.0 mL) was slowly treated with ICl (1M solution in dichloromethane) (0.202 mL, 0.202 mmol) and the mixture was stirred at ice bath temperature for 10 min. The mixture was quenched with saturated sodium thiosulfate and then extracted with dichloromethane. The extract was washed with saturated sodium bicarbonate, then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to a pale yellow solid (85 mg, 94%). LC / MS (m / z) ES ⁺ = 494 (M + 1).

Step 3: (S) -Ethyl 2- (2-benzyl-7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) -2- (tert- Butoxy) acetate

(S) -Ethyl 2- (2-benzyl-7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl in t-butyl acetate (3.0 mL) A suspension of) -2-hydroxyacetate (85 mg, 0.176 mmol) was treated with perchloric acid (0.041 mL, 0.688 mmol) to give a mixture that turned into an orange solution over several minutes. The mixture was stirred at ambient temperature for 45 minutes. The mixture was partitioned between EtOAc and 1N NaOH and the phases separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g column, 0-50% hexane / EtOAc) to give a pale yellow residue (56 mg, 59%). ¹ H NMR (400MHz, chloroform-d) δ = 7.39-7.28 (m, 5H), 5.90 (s, 1H), 4.79 (s, 2H), 4.39 (s, 2H), 4.26-4.07 (m, 2H) , 3.75-3.52 (m, 2H), 2.35 (s, 3H), 2.31 (s, 3H), 1.25-1.17 (m, 12H); LC / MS (m / z) ES ⁺ = 550 (M + 1) .

Step 4: (S) -ethyl 2- (2-benzyl-5,8-dimethyl-3-oxo-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2 -(tert-Butoxy) acetate

(S) -Ethyl 2- (2-benzyl-7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-6 in N, N-dimethylformamide (1.0 mL) -Yl) -2- (tert-butoxy) acetate (25.5 mg, 0.046 mmol) was added to p-tolylboronic acid (12.62 mg, 0.093 mmol), K ₃ PO ₄ (29.6 mg, 0.139 mmol), MePhos (3.38 mg, 9.28 μmol) and finally Pd ₂ dba ₃ (8.50 mg, 9.28 μmol) was added to degas. The mixture was degassed for several minutes and then stirred at 80 ° C. overnight. The mixture was cooled to ambient temperature and diluted with EtOAc, washed with water, then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give a pale yellow residue (11.8 mg, 50%). ¹ H NMR (400MHz, chloroform-d) δ = 7.38-7.15 (m, 8H), 7.05-6.98 (m, 1H), 4.97 (s, 1H), 4.81 (s, 2H), 4.41-4.33 (m, 2H), 4.25-4.04 (m, 2H), 3.78-3.61 (m, 2H), 2.42 (s, 3H), 2.33 (s, 3H), 1.74 (s, 3H), 1.23 (t, J = 7.1 Hz , 3H), 0.98-0.90 (m, 9H); LC / MS (m / z) ES ⁺ = 514 (M + 1).

Step 5: (S) -2- (2-Benzyl-5,8-dimethyl-3-oxo-7- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2- (tert-Butoxy) acetic acid

(S) -Ethyl 2- (2-benzyl-5,8-dimethyl-3-oxo-7- (p-tolyl) -1,2,3,4 in ethanol (0.5 mL) and tetrahydrofuran (0.5 mL) A mixture of -tetrahydroisoquinolin-6-yl) -2- (tert-butoxy) acetate (11.8 mg, 0.023 mmol) was treated with 2M LiOH (0.3 mL, 0.046 mmol). The mixture was heated to 70 ° C. and stirred for 10 hours, then stirred overnight at ambient temperature. The mixture was concentrated, diluted with 1N HCl and then extracted with EtOAc. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to a pale yellow residue. The residue was purified by reverse phase HPLC to give a white solid (3.1 mg, 28%). ¹ H NMR (400MHz, chloroform-d) δ = 7.40-7.18 (m, 8H), 7.07-6.98 (m, 1H), 5.15 (s, 1H), 4.88-4.75 (m, 2H), 4.36 (s, 2H), 3.81-3.59 (m, 2H), 2.41 (s, 3H), 2.26 (s, 3H), 1.77 (s, 3H), 0.98 (s, 9H); LC / MS (m / z) ES ⁺ = 486 (M + 1).

[Example 102]
(S) (M) -2- (2-Benzyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-3-oxo-1,2,3,4-tetrahydro Isoquinolin-6-yl) -2- (tert-butoxy) acetic acid

The title compound was prepared from (8-fluoro-5-methylchroman-6-yl) boronic acid in a manner similar to that described in Example 101 and isolated as a white solid after reverse phase HPLC. . ¹ H NMR (400MHz, chloroform-d) δ = 7.39-7.26 (m, 5H), 6.66 (d, J = 11.4 Hz, 1H), 5.08 (br. S., 1H), 4.90-4.83 (m, 1H ), 4.81-4.74 (m, 1H), 4.37 (s, 2H), 4.26 (t, J = 5.0 Hz, 2H), 3.73 (s, 2H), 2.76-2.58 (m, 2H), 2.29 (s, 3H), 2.17-2.07 (m, 2H), 1.82 (s, 3H), 1.66 (s, 3H), 1.12 (s, 9H); LC / MS (m / z) ES ⁺ = 560 (M + 1) .

[Example 103]
(S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -2- (3-fluorophenyl) -5,8-dimethyl -3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: N- (but-2-yn-1-yl) -3-fluoroaniline

To a solution of 3-fluoroaniline (3.0 g, 27.0 mmol) and K ₂ CO ₃ (3.73 g, 27.0 mmol) in DMF (50 mL) was added 1-bromobut-2-yne (3.95 g, 29.7 mmol) at 0 ° C. It was. After stirring at room temperature overnight, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 20% EtOAc in PE) The title compound (2.0 g, 45% yield) was obtained as a colorless oil. LC-MS (ESI): m / z (M + 1) = 164.86.

Step 2: N- (but-2-yn-1-yl) -N- (3-fluorophenyl) pent-3-inamide

To a mixture of N- (but-2-yn-1-yl) -3-fluoroaniline (2.0 g, 12.4 mmol), penta-3-ynoic acid (1.82 g, 18.6 mmol) in DMF (20 mL) was added T. ₃ P (50% solution in EtOAc, 19.7 g, 31.0 mmol) and DIPEA (5.6 g, 43.4 mmol) were added. After stirring at room temperature for 3 hours, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 20% EtOAc in PE) To give the title compound (2.0 g, 66% yield) as a yellow oil. LC-MS (ESI): m / z (M + 1) = 244.40.

Step 3: ethyl (S) -2- (2- (3-fluorophenyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl ) -2-Hydroxyacetate

A mixture of Rh (cod) ₂ BF ₄ (171 mg, 0.42 mmol) and BINAP (261 mg, 0.42 mmol) in DCM (5 mL) was stirred under H ₂ atmosphere for 6 hours at room temperature. After concentration, the resulting mixture was dissolved in DCE (5 mL) and ethyl (S) -2-hydroxy-4- (trimethylsilyl) but-3-inoate (823 mg, 4.2 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 80 ° C. and N- (but-2-yn-1-yl) -N- (3-fluorophenyl) pent-3-inamide (500 mg, 2.1 mmol) was added to the DCE solution. (5 mL) was added over 3 hours. After stirring at 80 ° C. for 30 minutes, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (250 mg, 27% yield) was obtained. LC-MS (ESI): m / z (M + 1) = 444.32.

Step 4: Ethyl (S) -2- (2- (3-fluorophenyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)- 2-hydroxyacetate

Ethyl (S) -2- (2- (3-fluorophenyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2 To a solution of hydroxyacetate (100 mg, 0.23 mmol) in DCM (2 mL) at 0 ° C. was added ICl (2.5 M solution in DCM, 0.1 mL, 0.25 mmol). After stirring at 0 ° C. for 10 minutes, the resulting mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a crude product that was used in the next step without further purification.

Step 5: Ethyl (S) -2- (tert-butoxy) -2- (2- (3-fluorophenyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4- Tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (2- (3-fluorophenyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) -2-hydroxy To a solution of acetate (crude product from the previous step, 0.23 mmol) in t-BuOAc (2 mL) was added HClO ₄ (20 mg, 0.2 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (90 mg, 71% yield over 2 steps). LC-MS (ESI): m / z (M + 1) = 554.53.

Step 6: Ethyl (2S) -2- (tert-butoxy) -2- (7- (8-fluoro-5-methylchroman-6-yl) -2- (3-fluorophenyl) -5,8-dimethyl -3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (tert-butoxy) -2- (2- (3-fluorophenyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3 in dioxane (2 mL) , 4-Tetrahydroisoquinolin-6-yl) acetate (90 mg, 0.16 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (136 mg, 0.65 mmol), Pd (Pt-Bu ₃ ) ₂ ( A mixture of 16 mg, 0.032 mmol) and Cs ₂ CO ₃ (211 mg, 0.65 mmol) was stirred at 90 ° C. for 15 min under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (70 mg, 73% yield). LC-MS (ESI): m / z (M + 1) = 592.62.

Step 7: (S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -2- (3-fluorophenyl) -5, 8-Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (7- (8-fluoro-5-methylchroman-6-yl) -2- (3-fluoro) in EtOH (1 mL) and dioxane (2 mL) (Phenyl) -5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (70 mg, 0.12 mmol) with LiOH (2.5 N, 0.47 mL, 1.2 mmol) added. After stirring for 1 hour at room temperature, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. The product is obtained as a mixture of diastereomers, which is further separated by chiral SFC (Superchiral S-OZ column using CO ₂ / EtOH = 70/30 (v / v)) The title compound (20 mg, 30% yield) was obtained. LC-MS (ESI): m / z (M + 1) = 564.27. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.69 (br, 1H), 7.47-7.36 (m, 1H), 7.22-7.09 (m , 2H), 7.02 (td, J = 8.5, 2.0 Hz, 1H), 6.70 (d, J = 11.3 Hz, 1H), 5.11 (s, 1H), 4.88-4.74 (m, 2H), 4.33-4.21 ( m, 2H), 3.88-3.73 (m, 2H), 2.77-2.62 (m, 2H), 2.34 (s, 3H), 2.17-2.06 (m, 2H), 1.87 (s, 3H), 1.79 (s, 3H), 1.14 (s, 9H).

[Example 104]
(S) -2- (tert-butoxy) -2-((R) -2-cyclohexyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-3-oxo- 1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: (S) -Ethyl 2- (2-cyclohexyl-5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2-hydroxy acetate

The title compound was prepared according to Step 101 of Example 101 with (S) -ethyl 2-hydroxy-4- (trimethylsilyl) but-3-inoate and N- (but-2-yn-1-yl) -N-cyclohexylpenta Prepared from 3-inamide in 30% yield. ¹ H NMR (400MHz, chloroform-d) δ 5.56 (s, 1H), 4.52-4.67 (m, 1H), 4.10-4.41 (m, 4H), 3.53 (s, 2H), 3.39 (s, 1 H) , 2.38 (s, 3H), 2.13 (s, 3H), 1.09-1.95 (m, 13H), 0.48 (s, 9 H).

Step 2: (S) -Ethyl 2- (tert-butoxy) -2- (2-cyclohexyl-7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-6- Yl) acetate

The title compound was made in 45% yield as a yellow foam in a manner similar to that described in Steps 2-3 of Example 101. ¹ H NMR (400MHz, chloroform-d) δ ppm 5.91 (s, 1H), 4.66-4.52 (m, 1H), 4.43-4.30 (m, 2H), 4.24-4.06 (m, 2H), 3.66-3.37 ( m, 2H), 2.53 (s, 3H), 2.30 (s, 3H), 1.92-1.79 (m, 2H), 1.79-1.63 (m, 4H), 1.57-1.36 (m, 4H), 1.31-1.07 ( m, 12H); LCMS (m / z) ES ⁺ = 542.3 (M + 1).

Step 3: (2S) -Ethyl 2- (tert-butoxy) -2- (2-cyclohexyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-3-oxo- 1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

(S) -Ethyl 2- (tert-butoxy) -2- (2-cyclohexyl-7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate A solution of (46 mg, 0.085 mmol) in 1,4-dioxane (1.5 mL) was added to (8-fluoro-5-methylchroman-6-yl) boronic acid (71.4 mg, 0.340 mmol), Cs2CO3 (83 mg, 0.255 mmol). And bis (tri-t-butylphosphine) palladium (0) (8.68 mg, 0.017 mmol) was degassed with N2. The reaction was stirred in an oil bath preheated to 90 ° C. for 10 minutes. The mixture was cooled to room temperature, diluted with EtOAc, washed with brine, dried over Na 2 SO 4, filtered and concentrated. Purify by column chromatography (0-80% EtOAc / hexanes) to give approximately 3: 1 (2S) -ethyl 2- (tert-butoxy) -2- (2-cyclohexyl-7- (8-fluoro-5 -Methylchroman-6-yl) -5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate isomers (M) (S) :( P) ( S) A mixture (39.6 mg, 0.068 mmol, 80% yield) was obtained as a yellow film. LCMS (m / z) ES ⁺ = 580.5 (M + 1).

Step 4: (S) -2- (tert-butoxy) -2-((R) -2-cyclohexyl-7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-3 -Oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

(2S) -Ethyl 2- (tert-butoxy) -2- (2-cyclohexyl-7- (8-fluoro-5-methylchroman-6) in 1,4-dioxane (1.5 mL) and ethanol (0.5 mL) A solution of -yl) -5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (67 mg, 0.116 mmol) was added with 2M LiOH (0.5 mL, 1.000 mmol). Treated and stirred at 100 ° C. for 12 hours. The reaction was cooled to room temperature and concentrated. The residue was diluted with EtOAc, washed with 1N HCl, brine, dried over Na 2 SO 4, filtered and concentrated. Purification by reverse phase HPLC (30-100% MeCN-0.1% formic acid / H2O-0.1% formic acid) gave the title compound ((M) (S) atropisomer) as a white solid. NMR showed approximately 5% (P) (S) atropisomer. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 6.61 (d, J = 11.4 Hz, 1H), 4.99 (s, 1H), 4.56-4.37 (m, 3H), 4.23 (t, J = 5.0 Hz, 2H), 3.60 (s, 2H), 2.73 (t, J = 6.4 Hz, 2H), 2.39 (s, 3H), 2.19-2.06 (m, 2H), 1.95-1.84 (m, 5H), 1.83-1.77 (m, 3H), 1.76-1.58 (m, 5H), 1.53-1.36 (m, 2H), 1.31-1.19 (m, 1H), 1.12-0.94 (m, 9H); LCMS (m / z) ES ⁺ = 552.4 (M + 1), ES - = 550.3 (M-1).

[Example 105]
(S) -2- (tert-butoxy) -2-((R) -2- (4,4-dimethylcyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8 -Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: tert-butylbut-2-yn-1-yl (4,4-dimethylcyclohexyl) carbamate

To a solution of tert-butyl (4,4-dimethylcyclohexyl) carbamate (2.21 g, 9.7 mmol) in DMF (20 mL) was added NaH (60%, 467 mg, 11.67 mmol) at 0 ° C. The resulting mixture was stirred at room temperature for 30 minutes before 1-bromobut-2-yne (1.42 g, 10.7 mmol) was introduced. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 20% EtOAc in PE) To give the title compound (1.0 g, 37% yield). LC-MS (ESI): m / z (M + 1) = 280.56.

Step 2: N- (but-2-yn-1-yl) -4,4-dimethylcyclohexane-1-amine

A mixture of tert-butylbut-2-yn-1-yl (4,4-dimethylcyclohexyl) carbamate (1.0 g, 3.58 mmol) in TEA (2 mL) and DCM (10 mL) was stirred at room temperature for 3 hours. The resulting mixture was concentrated, diluted with DCM and washed with saturated aqueous NaHCO ₃ solution. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (586 mg, 92% yield). LC-MS (ESI): m / z (M + 1) = 180.58.

Step 3: N- (but-2-yn-1-yl) -N- (4,4-dimethylcyclohexyl) pent-3-inamide

Of N- (but-2-yn-1-yl) -4,4-dimethylcyclohexane-1-amine (586 mg, 3.27 mmol), penta-3-ynoic acid (480 mg, 4.9 mmol) in THF (10 mL). To the mixture was added EDCI (936 mg, 4.9 mmol) and TEA (660 mg, 6.53 mmol). After stirring at room temperature for 3 hours, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-10% MeOH in DCM). To give the title compound (600 mg, 71% yield). LC-MS (ESI): m / z (M + 1) = 260.40.

Step 4: Ethyl (S) -2- (2- (4,4-dimethylcyclohexyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinoline-6 -Il) -2-Hydroxyacetate

A mixture of Rh (cod) ₂ BF ₄ (130 mg, 0.32 mmol) and BINAP (199 mg, 0.32 mmol) in DCM (5 mL) was stirred under H ₂ atmosphere for 6 hours at room temperature. After concentration, the resulting mixture was dissolved in DCE (5 mL) and ethyl (S) -2-hydroxy-4- (trimethylsilyl) but-3-inoate (648 mg, 3.2 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 80 ° C. and N- (but-2-yn-1-yl) -N- (4,4-dimethylcyclohexyl) pent-3-inamide (420 mg, 1.6 mmol) was added. DCE solution (5 mL) was added over 3 hours. After stirring at 80 ° C. for 30 minutes, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (290 mg 39% yield). LC-MS (ESI): m / z (M + 1) = 460.16.

Step 5: Ethyl (S) -2- (2- (4,4-dimethylcyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl ) -2-Hydroxyacetate

Ethyl (S) -2- (2- (4,4-dimethylcyclohexyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) To a solution of -2-hydroxyacetate (290 mg, 0.63 mmol) in DCM (2 mL) at 0 ° C. was added ICl (2.5 M solution in DCM, 0.27 mL, 0.68 mmol). After stirring at 0 ° C. for 10 minutes, the resulting mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a crude product that was used in the next step without further purification.

Step 6: Ethyl (S) -2- (tert-butoxy) -2- (2- (4,4-dimethylcyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3, 4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (2- (4,4-dimethylcyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) -2 To a solution of -hydroxyacetate (crude product from the previous step, 0.63 mmol) in t-BuOAc (4 mL) was added HClO ₄ (63 mg, 0.62 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (200 mg, 56% yield over 2 steps). LC-MS (ESI): m / z (M + 1) = 570.40.

Step 7: Ethyl (2S) -2- (tert-butoxy) -2- (2- (4,4-dimethylcyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8 -Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (tert-butoxy) -2- (2- (4,4-dimethylcyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2 in DMF (2 mL) , 3,4-Tetrahydroisoquinolin-6-yl) acetate (50 mg, 0.08 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (73 mg, 0.35 mmol), MePhos (7 mg, 0.018 mmol) , Pd ₂ (dba) ₃ (16 mg, 0.018 mmol) and Cs ₂ CO ₃ (58 mg, 0.18 mmol) were stirred at 90 ° C. overnight under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (41 mg, 85% yield). LC-MS (ESI): m / z (M + 1) = 608.90.

Step 8: (S) -2- (tert-butoxy) -2-((R) -2- (4,4-dimethylcyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl)- 5,8-Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (2- (4,4-dimethylcyclohexyl) -7- (8-fluoro-5-methylchroman) in EtOH (0.5 mL) and dioxane (1 mL) -6-yl) -5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (41 mg, 0.067 mmol) was added to LiOH (2.5 N, 0.27 mL, 0.67 mmol) was added. After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) afforded the title compound (15 mg, 38% yield). LC-MS (ESI): m / z (M + 1) = 580.56. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.65 (br, 1H), 6.70 (d, J = 11.3 Hz, 1H), 5.08 ( s, 1H), 4.57-4.49 (m, 1H), 4.42-4.24 (m, 4H), 3.67-3.56 (m, 2H), 2.76-2.62 (m, 2H), 2.28 (s, 3H), 2.17- 2.08 (m, 2H), 1.84 (d, J = 11.3 Hz, 6H), 1.78-1.68 (m, 2H), 1.59-1.47 (m, 6H), 1.11 (s, 9H), 0.96 (d, J = (11.0 Hz, 6H).

[Example 106]
(S) -2- (tert-butoxy) -2-((R) -2- (cyclohexylmethyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-3 -Oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: N- (cyclohexylmethyl) but-2-yn-1-amine

To cyclohexylmethanamine (10 g, 88.3 mmol) was slowly added 1-bromobut-2-yne (1.48 g, 11.1 mmol) at 0 ° C. After stirring at 0 ° C. for 30 minutes, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-10% MeOH in DCM). To give the title compound (1.5 g, 82% yield). LC-MS (ESI): m / z (M + 1) = 166.50.

Step 2: N- (but-2-yn-1-yl) -N- (cyclohexylmethyl) pent-3-inamide

To a mixture of N- (cyclohexylmethyl) but-2-yn-1-amine (1.5 g, 9.1 mmol), penta-3-ynoic acid (1.3 g, 13.6 mmol) in THF (20 mL) was added EDCI (2.6 g 13.6 mmol) and TEA (1.8 g, 17.8 mmol) were added. After stirring at room temperature for 3 hours, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (1.3 g, 59% yield) as a yellow oil. LC-MS (ESI): m / z (M + 1) = 246.44.

Step 3: Ethyl (S) -2- (2- (cyclohexylmethyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl)- 2-hydroxyacetate

A mixture of Rh (cod) ₂ BF ₄ (150 mg, 0.37 mmol) and BINAP (230 mg, 0.0.37 mmol) in DCM (5 mL) was stirred under H ₂ atmosphere for 6 hours at room temperature. After concentration, the resulting mixture was dissolved in DCE (5 mL) and ethyl (S) -2-hydroxy-4- (trimethylsilyl) but-3-inoate (734 mg, 3.7 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 80 ° C. and N- (but-2-yn-1-yl) -N- (cyclohexylmethyl) pent-3-inamide (450 mg, 1.8 mmol) was added to a DCE solution (5 mL ) Was added over 3 hours. After stirring at 80 ° C. for 30 min, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (150 mg 19% yield). LC-MS (ESI): m / z (M + 1) = 446.41.

Step 4: Ethyl (S) -2- (2- (cyclohexylmethyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) -2- Hydroxy acetate

Ethyl (S) -2- (2- (cyclohexylmethyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2-hydroxy To a solution of acetate (150 mg, 0.34 mmol) in DCM (2 mL) was added ICl (2.5 M solution in DCM, 0.15 mL, 0.37 mmol) at 0 ° C. After stirring at 0 ° C. for 10 minutes, the resulting mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a crude product that was used in the next step without further purification. LC-MS (ESI): m / z (M + 1) = 500.32.

Step 5: Ethyl (S) -2- (tert-butoxy) -2- (2- (cyclohexylmethyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinoline -6-yl) acetate

Ethyl (S) -2- (2- (cyclohexylmethyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) -2-hydroxyacetate ( To a solution of the crude product from the previous step, 0.34 mmol) in t-BuOAc (2 mL) was added HClO ₄ (34 mg, 0.34 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (68 mg, 36% yield over 2 steps). LC-MS (ESI): m / z (M + 1) = 556.71.

Step 6: (S) -Ethyl 2- (tert-butoxy) -2-((R) -2- (cyclohexylmethyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8 -Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (tert-butoxy) -2- (2- (cyclohexylmethyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4 in dioxane (2 mL) -Tetrahydroisoquinolin-6-yl) acetate (68 mg, 0.12 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (101 mg, 0.48 mmol), Pd (Pt-Bu ₃ ) ₂ (12 mg, 0.024 mmol) and Cs ₂ CO ₃ (156 mg, 0.48 mmol) were stirred at 90 ° C. for 15 minutes under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (15 mg, 21% yield). LC-MS (ESI): m / z (M + 1) = 594.72.

Step 7: (S) -2- (tert-butoxy) -2-((R) -2- (cyclohexylmethyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8- Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (2- (cyclohexylmethyl) -7- (8-fluoro-5-methylchroman-6-yl) in EtOH (0.5 mL) and dioxane (1 mL) ) -5,8-Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (15 mg, 0.025 mmol) was added LiOH (2.5 N, 0.1 mL, 0.25 mmol) It was. After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) gave the title compound (9 mg, 63% yield). LC-MS (ESI): m / z (M + 1) = 566.90. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.53 (br, 1H), 6.70 (d, J = 11.2 Hz, 1H), 5.08 ( s, 1H), 4.42 (s, 2H), 4.32-4.22 (m, 2H), 3.62 (s, 2H), 3.47-3.35 (m, 2H), 2.74-2.62 (m, 2H), 2.37-2.21 ( m, 3H), 2.12 (dd, J = 6.1, 3.8 Hz, 2H), 1.89-1.56 (m, 13H), 1.25-0.99 (m, 13H).

[Example 107]
(S) -2- (tert-butoxy) -2-((R) -2- (3-fluoro-2-methoxyphenyl) -7- (8-fluoro-5-methylchroman-6-yl) -5 , 8-Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: N- (but-2-yn-1-yl) -3-fluoro-2-methoxyaniline

To a mixture of 3-fluoro-2-methoxyaniline (1.0 g, 7.1 mmol) and K ₂ CO ₃ (1.04 g, 7.8 mmol) in DMF (15 mL) was added 1-bromobut-2-yne (981 mg, 7.1 mmol). And stirred overnight at room temperature. The resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 20% EtOAc in PE) To give the title compound (552 mg, 40% yield) as a yellow oil. LC-MS (ESI): m / z (M + 1) = 193.91.

Step 2: N- (but-2-yn-1-yl) -N- (3-fluoro-2-methoxyphenyl) pent-3-inamide

To a mixture of N- (but-2-yn-1-yl) -3-fluoro-2-methoxyaniline (552 mg, 2.8 mmol), penta-3-ynoic acid (421 mg, 4.3 mmol) in DMF (5 mL) , T ₃ P (50% solution in EtOAc, 4.5 g, 7.1 mmol) and DIPEA (1.3 g, 10 mmol) were added. After stirring at room temperature for 30 minutes, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 20% EtOAc in PE) To give the title compound (450 mg, 59% yield) as a yellow oil. LC-MS (ESI): m / z (M + 1) = 274.18.

Step 3: Ethyl (S) -2- (2- (3-fluoro-2-methoxyphenyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinoline -6-yl) -2-hydroxyacetate

A mixture of Rh (cod) ₂ BF ₄ (134 mg, 0.33 mmol) and BINAP (205 mg, 0.33 mmol) in DCM (5 mL) was stirred at room temperature for 6 hours under H ₂ atmosphere. After concentration, the resulting mixture was dissolved in DCE (5 mL) and ethyl (S) -2-hydroxy-4- (trimethylsilyl) but-3-inoate (662 mg, 3.3 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 80 ° C. and N- (but-2-yn-1-yl) -N- (3-fluoro-2-methoxyphenyl) pent-3-inamide (450 mg, 1.65 mmol) ) Was added as a DCE solution (5 mL) over 3 hours. After stirring at 80 ° C. for 30 minutes, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (130 mg 17% yield). LC-MS (ESI): m / z (M + 1) = 474.42.

Step 4: Ethyl (S) -2- (2- (3-fluoro-2-methoxyphenyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-6 -Il) -2-Hydroxyacetate

Ethyl (S) -2- (2- (3-fluoro-2-methoxyphenyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinoline-6- Yl) -2-hydroxyacetate (130 mg, 0.27 mmol) in DCM (2 mL) at 0 ° C. was added ICl (2.5 M solution in DCM, 0.11 mL, 0.27 mmol). After stirring at 0 ° C. for 10 minutes, the resulting mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a crude product that was used in the next step without further purification. LC-MS (ESI): m / z (M + 1) = 528.24.

Step 5: Ethyl (S) -2- (tert-butoxy) -2- (2- (3-fluoro-2-methoxyphenyl) -7-iodo-5,8-dimethyl-3-oxo-1,2, 3,4-Tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (2- (3-fluoro-2-methoxyphenyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) To a solution of 2-hydroxyacetate (crude product from previous step, 0.27 mmol) in t-BuOAc (2 mL) was added HClO ₄ (28 mg, 0.28 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (100 mg, 63% yield over 2 steps). LC-MS (ESI): m / z (M + 1) = 584.41.

Step 6: (S) -Ethyl 2- (tert-butoxy) -2-((R) -2- (3-fluoro-2-methoxyphenyl) -7- (8-fluoro-5-methylchroman-6- Yl) -5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (tert-butoxy) -2- (2- (3-fluoro-2-methoxyphenyl) -7-iodo-5,8-dimethyl-3-oxo-1 in dioxane (2 mL) , 2,3,4-Tetrahydroisoquinolin-6-yl) acetate (50 mg, 0.085 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (71 mg, 0.34 mmol), Pd (Pt-Bu ₃ ) A mixture of ₂ (8 mg, 0.017 mmol) and Cs ₂ CO ₃ (110 mg, 0.34 mmol) was stirred at 90 ° C. for 15 minutes under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (35 mg, 66% yield). LC-MS (ESI): m / z (M + 1) = 622.84.

Step 7: (S) -2- (tert-butoxy) -2-((R) -2- (3-fluoro-2-methoxyphenyl) -7- (8-fluoro-5-methylchroman-6-yl) ) -5,8-Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (2- (3-fluoro-2-methoxyphenyl) -7- (8-fluoro-5-) in EtOH (0.5 mL) and dioxane (1 mL) Methylchroman-6-yl) -5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (35 mg, 0.056 mmol) in a mixture of LiOH (2.5 N, 0.23 mL 0.56 mmol) was added. After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) afforded the title compound (13 mg, 39% yield). LC-MS (ESI): m / z (M + 1) = 594.66. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.60 (br, 1H), 7.18-6.98 (m, 3H), 6.70 (d, J = 11.5 Hz, 1H), 5.12 (s, 1H), 4.81-4.60 (m, 2H), 4.36-4.17 (m, 2H), 3.92 (d, J = 1.7 Hz, 3H), 3.81 (s, 2H) , 2.77-2.62 (m, 2H), 2.33 (s, 3H), 2.17-2.07 (m, 2H), 1.87 (s, 3H), 1.75 (s, 3H), 1.14 (s, 9H).

[Example 108]
(S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-3-oxo-2- (tetrahydro -2H-pyran-4-yl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: tert-Butylbut-2-yn-1-yl (tetrahydro-2H-pyran-4-yl) carbamate

To a solution of tert-butyl (tetrahydro-2H-pyran-4-yl) carbamate (1 g, 5.0 mmol) in THF (10 mL) was added NaH (60%, 240 mg, 6.0 mmol) at 0 ° C. After the reaction mixture was stirred at 0 ° C. for 30 min, 1-bromobut-2-yne (990 mg, 7.5 mmol) was added. After stirring at room temperature overnight, the resulting mixture was quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 20% EtOAc in PE) To give the title compound (1.0 g, 79% yield). LC-MS (ESI): m / z (M + 1) = 254.33.

Step 2: N- (but-2-yn-1-yl) tetrahydro-2H-pyran-4-amine

A mixture of tert-butylbut-2-in-1-yl (tetrahydro-2H-pyran-4-yl) carbamate (1.0 g, 3.16 mmol) in TEA (10 mL) and DCM (20 mL) was stirred at room temperature for 2 hours. did. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in DCM, washed with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (660 mg, 99% yield), which was used in the next step without further purification. LC-MS (ESI): m / z (M + 1) = 154.41.

Step 3: N- (but-2-yn-1-yl) -N- (tetrahydro-2H-pyran-4-yl) pent-3-inamide

To a mixture of N- (but-2-yn-1-yl) tetrahydro-2H-pyran-4-amine (600 mg, 3.9 mmol), penta-3-ynoic acid (578 mg, 5.9 mmol) in THF (20 mL) , EDCI (1.1 g, 5.9 mmol) and TEA (789 mg, 7.8 mmol) were added. After stirring at room temperature for 3 hours, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 20% EtOAc in PE) To give the title compound (636 mg, 70% yield). LC-MS (ESI): m / z (M + 1) = 234.47.

Step 4: Ethyl (S) -2- (5,8-dimethyl-3-oxo-2- (tetrahydro-2H-pyran-4-yl) -7- (trimethylsilyl) -1,2,3,4-tetrahydro Isoquinolin-6-yl) -2-hydroxyacetate

A mixture of Rh (cod) ₂ BF ₄ (219 mg, 0.54 mmol) and BINAP (336 mg, 0.54 mmol) in DCM (5 mL) was stirred at room temperature for 6 hours under H ₂ atmosphere. After concentration, the resulting mixture was dissolved in DCE (5 mL) and ethyl (S) -2-hydroxy-4- (trimethylsilyl) but-3-inoate (1.1 g, 5.4 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 80 ° C. and N- (but-2-yn-1-yl) -N- (tetrahydro-2H-pyran-4-yl) pent-3-inamide (636 mg, 2.7 mg mmol) was added as a DCE solution (5 mL) over 3 h. After stirring at 80 ° C. for 30 minutes, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (640 mg 55% yield). LC-MS (ESI): m / z (M + 1) = 434.94.

Step 5: Ethyl (S) -2-hydroxy-2- (7-iodo-5,8-dimethyl-3-oxo-2- (tetrahydro-2H-pyran-4-yl) -1,2,3,4 -Tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (5,8-dimethyl-3-oxo-2- (tetrahydro-2H-pyran-4-yl) -7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinoline-6 To a solution of -yl) -2-hydroxyacetate (64 mg, 0.15 mmol) in DCM (1 mL) at 0 ° C. was added ICl (2.5 M solution in DCM, 0.06 mL, 0.15 mmol). After stirring at 0 ° C. for 10 minutes, the resulting mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a crude product that was used in the next step without further purification.

Step 6: Ethyl (S) -2- (tert-butoxy) -2- (7-iodo-5,8-dimethyl-3-oxo-2- (tetrahydro-2H-pyran-4-yl) -1,2 , 3,4-Tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2-hydroxy-2- (7-iodo-5,8-dimethyl-3-oxo-2- (tetrahydro-2H-pyran-4-yl) -1,2,3,4-tetrahydroisoquinoline To a solution of -6-yl) acetate (crude product from the previous step, 0.15 mmol) in t-BuOAc (2 mL) was added HClO ₄ (15 mg, 0.15 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (50 mg, 61% yield over 2 steps). LC-MS (ESI): m / z (M + 1) = 544.28.

Step 7: (S) -Ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-3-oxo- 2- (Tetrahydro-2H-pyran-4-yl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (tert-butoxy) -2- (7-iodo-5,8-dimethyl-3-oxo-2- (tetrahydro-2H-pyran-4-yl)-in dioxane (2 mL) 1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (50 mg, 0.09 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (38 mg, 0.18 mmol), Pd (Pt- A mixture of Bu ₃ ) ₂ (9 mg, 0.018 mmol) and Cs ₂ CO ₃ (60 mg, 0.18 mmol) was stirred at 90 ° C. for 15 minutes under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (35 mg, 67% yield). LC-MS (ESI): m / z (M + 1) = 582.53.

Step 8: (S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-3-oxo-2 -(Tetrahydro-2H-pyran-4-yl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl in EtOH (0.5 mL) and dioxane (1 mL) LiOH (2.5N, 0.24) was added to a mixture of -3-oxo-2- (tetrahydro-2H-pyran-4-yl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (35 mg, 0.06 mmol). mL, 0.6 mmol) was added. After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) gave the title compound (16 mg, 48% yield). LC-MS (ESI): m / z (M + 1) = 554.48. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.62 (br, 1H), 6.69 (d, J = 11.1 Hz, 1H), 5.09 ( s, 1H), 4.97-4.89 (m, 1H), 4.41-4.24 (m, 4H), 4.07 (d, J = 11.6 Hz, 2H), 3.70-3.52 (m, 4H), 2.76-2.63 (m, 2H), 2.29 (s, 3H), 2.18-2.07 (m, 2H), 2.00-1.77 (m, 8H), 1.71-1.64 (m, 2H), 1.12 (s, 9H).

[Example 109]
((S) -2- (tert-butoxy) -2-((R) -2-cyclohexyl-7- (8-fluoro-5-methylchroman-6-yl) -4,4,5,8-tetra Methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: N- (but-2-yn-1-yl) cyclohexaneamine

To cyclohexaneamine (5 g, 50.5 mmol) was slowly added 1-bromobut-2-yne (1 g, 7.5 mmol) at 0 ° C. After stirring at 0 ° C. for 30 minutes, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-10% MeOH in DCM). To give the title compound (1.5 g, 80% yield). LC-MS (ESI): m / z (M + 1) = 152.32.

Step 2: N- (but-2-yn-1-yl) -N-cyclohexyl-2,2-dimethylpent-3-inamide

To a solution of 2,2-dimethylpent-3-ynoic acid (275 mg, 2.18 mmol) in DCM (5 mL) at 0 ° C. was added (COCl) ₂ (369 mg, 2.91 mmol) and 1 drop of DMF. After stirring at 0 ° C. for 2 hours, the resulting mixture was concentrated and the residue was dissolved in DCM to give N- (but-2-yn-1-yl) cyclohexaneamine (220 mg, 1.46 mmol) in DCM ( 5 mL) was introduced into the solution. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (225 mg, 60% yield) was obtained as a yellow oil. LC-MS (ESI): m / z (M + 1) = 260.32.

Step 3: ethyl (S) -2- (2-cyclohexyl-4,4,5,8-tetramethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl ) -2-Hydroxyacetate

A mixture of Rh (cod) ₂ BF ₄ (36 mg, 0.09 mmol) and BINAP (56 mg, 0.09 mmol) in DCM (2 mL) was stirred under H ₂ atmosphere for 6 hours at room temperature. After concentration, the resulting mixture was dissolved in DCE (5 mL) and ethyl (S) -2-hydroxy-4- (trimethylsilyl) but-3-inoate (184 mg, 0.92 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 80 ° C. and N- (but-2-yn-1-yl) -N-cyclohexyl-2,2-dimethylpent-3-inamide (120 mg, 0.46 mmol) was added to DCE. Added as a solution (5 mL) over 3 hours. After stirring at 80 ° C. for 30 minutes, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (53 mg 25% yield). LC-MS (ESI): m / z (M + 1) = 460.54.

Step 4: Ethyl (S) -2- (2-cyclohexyl-7-iodo-4,4,5,8-tetramethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)- 2-hydroxyacetate

Ethyl (S) -2- (2-cyclohexyl-4,4,5,8-tetramethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) -2 To a solution of hydroxyacetate (53 mg, 0.12 mmol) in DCM (2 mL) at 0 ° C. was added ICl (2.5 M solution in DCM, 0.05 mL, 0.12 mmol). After stirring at 0 ° C. for 10 minutes, the resulting mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a crude product that was used in the next step without further purification. LC-MS (ESI): m / z (M + 1) = 514.30.

Step 5: Ethyl (S) -2- (tert-butoxy) -2- (2-cyclohexyl-7-iodo-4,4,5,8-tetramethyl-3-oxo-1,2,3,4- Tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (2-cyclohexyl-7-iodo-4,4,5,8-tetramethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) -2-hydroxy To a solution of acetate (crude product from the previous step, 0.12 mmol) in t-BuOAc (2 mL) was added HClO ₄ (12 mg, 0.12 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (21 mg, 31% yield over 2 steps). LC-MS (ESI): m / z (M + 1) = 570.43.

Step 6: (S) -ethyl 2- (tert-butoxy) -2-((R) -2-cyclohexyl-7- (8-fluoro-5-methylchroman-6-yl) -4,4,5, 8-tetramethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (tert-butoxy) -2- (2-cyclohexyl-7-iodo-4,4,5,8-tetramethyl-3-oxo-1,2,3 in dioxane (2 mL) , 4-Tetrahydroisoquinolin-6-yl) acetate (21 mg, 0.037 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (31 mg, 0.147 mmol), Pd (Pt-Bu ₃ ) ₂ ( A mixture of 4 mg, 0.007 mmol) and Cs ₂ CO ₃ (36 mg, 0.111 mmol) was stirred at 90 ° C. for 15 min under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (20 mg, 89% yield). LC-MS (ESI): m / z (M + 1) = 608.71.

Step 7: (S) -2- (tert-butoxy) -2-((R) -2-cyclohexyl-7- (8-fluoro-5-methylchroman-6-yl) -4,4,5,8 -Tetramethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (2-cyclohexyl-7- (8-fluoro-5-methylchroman-6-yl) -4 in EtOH (0.5 mL) and dioxane (1 mL) , 4,5,8-Tetramethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (20 mg, 0.033 mmol) was added to LiOH (2.5 N, 0.15 mL, 0.37 mmol). ) Was added. After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) gave the title compound (9 mg, 47% yield). LC-MS (ESI): m / z (M + 1) = 580.45. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.57 (br, 1H), 6.67 (d, J = 10.9 Hz, 1H), 5.15 ( s, 1H), 4.65-4.55 (m, 1H), 4.39-4.21 (m, 4H), 2.75-2.62 (m, 2H), 2.49 (s, 3H), 2.17-2.08 (m, 2H), 1.81- 1.47 (m, 22H), 1.11 (s, 9H).

[Example 110]
((S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -2-isobutyl-5,8-dimethyl-3-oxo -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: N-isobutylbut-2-in-1-amine

To 2-methylpropan-1-amine (5 g, 68.4 mmol) was slowly added 1-bromobut-2-yne (1.82 g, 13.7 mmol) at 0 ° C. After stirring at 0 ° C. for 10 minutes, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (850 mg, 50% yield) as a yellow oil. LC-MS (ESI): m / z (M + 1) = 126.24.

Step 2: N- (but-2-yn-1-yl) -N-isobutylpent-3-inamide

To a mixture of N-isobutylbut-2-in-1-amine (436 mg, 3.5 mmol), penta-3-ynoic acid (513 mg, 5.2 mmol) in THF (10 mL), EDCI (1.33 g, 6.97 mmol) and TEA (2 mL, 13.9 mmol) was added. After stirring at room temperature for 1 hour, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 30% EtOAc in PE) To give the title compound (365 mg, 51% yield) as a yellow oil. LC-MS (ESI): m / z (M + 1) = 206.32.

Step 3: Ethyl (S) -2-hydroxy-2- (2-isobutyl-5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

A mixture of Rh (cod) ₂ BF ₄ (146 mg, 0.36 mmol) and BINAP (224 mg, 0.36 mmol) in DCM (5 mL) was stirred at room temperature for 6 hours under H ₂ atmosphere. After concentration, the resulting mixture was dissolved in DCE (5 mL) and ethyl (S) -2-hydroxy-4- (trimethylsilyl) but-3-inoate (712 mg, 3.56 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 80 ° C. and N- (but-2-yn-1-yl) -N-isobutylpent-3-inamide (365 mg, 1.78 mmol) was added as a DCE solution (5 mL) 3 Added over time. After stirring at 80 ° C. for 30 minutes, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (120 mg 17% yield). LC-MS (ESI): m / z (M + 1) = 406.56.

Step 4: Ethyl (S) -2-hydroxy-2- (7-iodo-2-isobutyl-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2-hydroxy-2- (2-isobutyl-5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (120 mg , 0.296 mmol) in DCM (2 mL) at 0 ° C. was added ICl (2.5 M solution in DCM, 0.12 mL, 0.296 mmol). After stirring at 0 ° C. for 10 minutes, the resulting mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ and filtered to give the title compound as a crude product that was used in the next step without further purification.

Step 5: Ethyl (S) -2- (tert-butoxy) -2- (7-iodo-2-isobutyl-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-6- Yl) acetate

Ethyl (S) -2-hydroxy-2- (7-iodo-2-isobutyl-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (previous step To a solution of the crude product from (0.296 mmol) in t-BuOAc (2 mL) was added HClO ₄ (30 mg, 0.30 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (130 mg, 85% yield over 2 steps). LC-MS (ESI): m / z (M + 1) = 516.43.

Step 6: (S) -Ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -2-isobutyl-5,8-dimethyl- 3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (tert-butoxy) -2- (7-iodo-2-isobutyl-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinoline in dioxane (2 mL) -6-yl) acetate (50 mg, 0.097 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (81 mg, 0.388 mmol), Pd (Pt-Bu ₃ ) ₂ (10 mg, 0.0194 mmol) And Cs ₂ CO ₃ (95 mg, 0.291 mmol) was stirred at 90 ° C. for 15 minutes under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (42 mg, 78% yield). LC-MS (ESI): m / z (M + 1) = 554.83.

Step 7: ((S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -2-isobutyl-5,8-dimethyl- 3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (7- (8-fluoro-5-methylchroman-6-yl) -2-isobutyl-5 in EtOH (0.5 mL) and dioxane (1 mL) , 8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (42 mg, 0.076 mmol) was added LiOH (2.5 N, 0.3 mL, 0.75 mmol). After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) afforded the title compound (22 mg, 55% yield). LC-MS (ESI): m / z (M + 1) = 526.25. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.57 (br, 1H), 6.70 (d, J = 11.2 Hz, 1H), 5.09 ( s, 1H), 4.42 (s, 2H), 4.32-4.21 (m, 2H), 3.63 (d, J = 5.0 Hz, 2H), 3.48-3.32 (m, 2H), 2.76-2.62 (m, 2H) , 2.28 (s, 3H), 2.18-2.03 (m, 3H), 1.83 (d, J = 24.3 Hz, 6H), 1.12 (s, 9H), 0.95 (d, J = 6.6 Hz, 6H).

[Example 111]
(2S) -2- (tert-butoxy) -2-((7R) -2- (3,3-dimethylcyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8 -Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: N- (but-2-yn-1-yl) -3,3-dimethylcyclohexane-1-amine

To 3,3-dimethylcyclohexane-1-amine (5 g, 39.4 mmol) was slowly added 1-bromobut-2-yne (1.04 g, 7.85 mmol) at 0 ° C. After stirring at 0 ° C. for 10 minutes, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (1.03 g, 73% yield) as a yellow oil. LC-MS (ESI): m / z (M + 1) = 180.31.

Step 2: N- (but-2-yn-1-yl) -N- (3,3-dimethylcyclohexyl) pent-3-inamide

Of N- (but-2-yn-1-yl) -3,3-dimethylcyclohexane-1-amine (460 mg, 2.57 mmol), penta-3-ynoic acid (377 mg, 3.85 mmol) in THF (10 mL). To the mixture was added EDCI (984 mg, 5.13 mmol) and TEA (1.04 g, 10.26 mmol). After stirring at room temperature for 1 hour, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 30% EtOAc in PE) To give the title compound (480 mg, 61% yield) as a yellow oil. LC-MS (ESI): m / z (M + 1) = 260.41.

Step 3: ethyl (2S) -2- (2- (3,3-dimethylcyclohexyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinoline-6 -Il) -2-Hydroxyacetate

A mixture of Rh (cod) ₂ BF ₄ (128 mg, 0.315 mmol) and BINAP (196 mg, 0.315 mmol) in DCM (5 mL) was stirred at room temperature for 6 hours under H ₂ atmosphere. After concentration, the resulting mixture was dissolved in DCE (5 mL) and ethyl (S) -2-hydroxy-4- (trimethylsilyl) but-3-inoate (630 mg, 3.15 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 80 ° C. and N- (but-2-yn-1-yl) -N- (3,3-dimethylcyclohexyl) pent-3-inamide (408 mg, 1.57 mmol) was added. DCE solution (5 mL) was added over 3 hours. After stirring at 80 ° C. for 30 minutes, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (270 mg 20% yield). LC-MS (ESI): m / z (M + 1) = 460.85.

Step 4: Ethyl (2S) -2- (2- (3,3-dimethylcyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl ) -2-Hydroxyacetate

Ethyl (2S) -2- (2- (3,3-dimethylcyclohexyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) To a solution of -2-hydroxyacetate (270 mg, 0.587 mmol) in DCM (10 mL) was added ICl (2.5 M solution in DCM, 0.23 mL, 0.58 mmol) at 0 ° C. After stirring at 0 ° C. for 10 minutes, the resulting mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a crude product that was used in the next step without further purification. LC-MS (ESI): m / z (M + 1) = 514.60.

Step 5: Ethyl (2S) -2- (tert-butoxy) -2- (2- (3,3-dimethylcyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3, 4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (2S) -2- (2- (3,3-dimethylcyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) -2 To a solution of -hydroxyacetate (crude product from the previous step, 0.587 mmol) in t-BuOAc (5 mL) was added HClO ₄ (60 mg, 0.60 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (100 mg, 30% yield over 2 steps). LC-MS (ESI): m / z (M + 1) = 570.62.

Step 6: (2S) -ethyl 2- (tert-butoxy) -2-((7R) -2- (3,3-dimethylcyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (2S) -2- (tert-butoxy) -2- (2- (3,3-dimethylcyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2 in dioxane (2 mL) , 3,4-Tetrahydroisoquinolin-6-yl) acetate (50 mg, 0.088 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (74 mg, 0.35 mmol), Pd (Pt-Bu ₃ ) A mixture of ₂ (9 mg, 0.0176 mmol) and Cs ₂ CO ₃ (86 mg, 0.263 mmol) was stirred at 90 ° C. for 15 minutes under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (50 mg, 94% yield). LC-MS (ESI): m / z (M + 1) = 608.84.

Step 7: (2S) -2- (tert-butoxy) -2-((7R) -2- (3,3-dimethylcyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl)- 5,8-Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (2- (3,3-dimethylcyclohexyl) -7- (8-fluoro-5-methylchroman) in EtOH (0.5 mL) and dioxane (1 mL) -6-yl) -5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (50 mg, 0.0823 mmol) to a mixture of LiOH (2.5 N, 0.33 mL, 0.823 mmol) was added. After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) gave the title compound (15.6 mg, 33% yield). LC-MS (ESI): m / z (M + 1) = 580.46. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.57 (br, 1H), 6.69 (d, J = 11.2 Hz, 1H), 5.07 ( s, 1H), 4.89-4.78 (m, 1H), 4.44-4.17 (m, 4H), 3.69-3.48 (m, 2H), 2.78-2.62 (m, 2H), 2.28 (s, 3H), 2.17- 2.08 (m, 2H), 1.84 (d, J = 13.5 Hz, 6H), 1.66-1.37 (m, 8H), 1.24-0.86 (m, 15H).

[Example 112]
(S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-2- (1-methylpiperidine- 4-yl) -3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: tert-butyl 4- (but-2-in-1-ylamino) piperidine-1-carboxylate

To tert-butyl 4-aminopiperidine-1-carboxylate (5 g, 25.0 mmol), 1-bromobut-1-yne (1.0 g, 7.52 mmol) was slowly added at 0 ° C. After stirring at 0 ° C. for 30 minutes, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-10% MeOH in DCM). To give the title compound (1.01 g, 35% yield) as a white solid. LC-MS (ESI): m / z (M + 1) = 253.20.

Step 2: tert-Butyl 4- (N- (but-2-yn-1-yl) pent-3-inamido) piperidine-1-carboxylate

To a mixture of tert-butyl 4- (but-2-yn-1-ylamino) piperidine-1-carboxylate (500 mg, 1.98 mmol), penta-3-ynoic acid (291 mg, 2.97 mmol) in THF (10 mL) , EDCI (597 mg, 2.97 mmol) and TEA (400 mg, 3.96 mmol) were added. After stirring at room temperature for 3 hours, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-10% MeOH in DCM). To give the title compound (500 mg, 75% yield) as a white solid. LC-MS (ESI): m / z (M + 1) = 333.26.

Step 3: tert-butyl (S) -4- (6- (2-ethoxy-1-hydroxy-2-oxoethyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -3,4-dihydro Isoquinolin-2 (1H) -yl) piperidine-1-carboxylate

A mixture of Rh (cod) ₂ BF ₄ (146 mg, 0.36 mmol) and BINAP (224 mg, 0.36 mmol) in DCM (10 mL) was stirred at room temperature for 6 hours under H ₂ atmosphere. After concentration, the resulting mixture was dissolved in DCE (10 mL) and ethyl (S) -2-hydroxy-4- (trimethylsilyl) but-3-inoate (720 mg, 3.6 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 80 ° C. and tert-butyl 4- (N- (but-2-yn-1-yl) pent-3-inamido) piperidine-1-carboxylate (500 mg, 1.8 mmol) ) Was added as a DCE solution (10 mL) over 3 hours. After stirring at 80 ° C. for 30 minutes, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (200 mg 25% yield). LC-MS (ESI): m / z (M + 1) = 533.41.

Step 4: tert-Butyl (S) -4- (6- (2-ethoxy-1-hydroxy-2-oxoethyl) -7-iodo-5,8-dimethyl-3-oxo-3,4-dihydroisoquinoline- 2 (1H) -yl) piperidine-1-carboxylate

tert-butyl (S) -4- (6- (2-ethoxy-1-hydroxy-2-oxoethyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -3,4-dihydroisoquinoline-2 To a solution of (1H) -yl) piperidine-1-carboxylate (200 mg, 0.38 mmol) in DCM (2 mL) was added ICl (2.5 M solution in DCM, 0.15 mL, 0.38 mmol) at 0 ° C. After stirring at 0 ° C. for 10 minutes, the resulting mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a crude product that was used in the next step without further purification. LC-MS (ESI): m / z (M + 1) = 587.22.

Step 5: Ethyl (S) -2-hydroxy-2- (7-iodo-5,8-dimethyl-3-oxo-2- (piperidin-4-yl) -1,2,3,4-tetrahydroisoquinoline- 6-yl) acetate

  tert-butyl (S) -4- (6- (2-ethoxy-1-hydroxy-2-oxoethyl) -7-iodo-5,8-dimethyl-3-oxo-3,4-dihydroisoquinoline-2 (1H To a solution of) -yl) piperidine-1-carboxylate (crude product from the previous step, 0.38 mmol) in DCM (2 mL) was added 4N HCl in dioxane (2 mL). After stirring for 1 hour at room temperature, the resulting mixture was concentrated to give the title compound as a crude product (HCl salt), which was used in the next step without further purification. LC-MS (ESI): m / z (M + 1) = 487.25.

Step 6: Ethyl (S) -2- (tert-butoxy) -2- (7-iodo-5,8-dimethyl-3-oxo-2- (piperidin-4-yl) -1,2,3,4 -Tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2-hydroxy-2- (7-iodo-5,8-dimethyl-3-oxo-2- (piperidin-4-yl) -1,2,3,4-tetrahydroisoquinolin-6-yl To a solution of acetate (crude product from previous step, 0.38 mmol) in t-BuOAc (2 mL) was added HClO ₄ (38 mg, 0.38 mmol). After stirring at room temperature for 3 hours, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-10% MeOH in DCM). To give the title compound (44 mg, 21% yield over 3 steps). LC-MS (ESI): m / z (M + 1) = 543.62.

Step 7: Ethyl (S) -2- (tert-butoxy) -2- (7-iodo-5,8-dimethyl-2- (1-methylpiperidin-4-yl) -3-oxo-1,2, 3,4-Tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (tert-butoxy) -2- (7-iodo-5,8-dimethyl-3-oxo-2- (piperidin-4-yl) -1,2, in DCE (2 mL) A mixture of 3,4-tetrahydroisoquinolin-6-yl) acetate (44 mg, 0.08 mol), paraformaldehyde (3.6 mg, 0.12 mmol) and NaBH (OAc) ₃ (37 mg, 0.176 mmol) was stirred at room temperature for 48 hours. The resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-10% MeOH in DCM). To give the title compound (32 mg, 72% yield). LC-MS (ESI): m / z (M + 1) = 557.41.

Step 8: (S) -Ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-2- (1) -Methylpiperidin-4-yl) -3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (tert-butoxy) -2- (7-iodo-5,8-dimethyl-2- (1-methylpiperidin-4-yl) -3-oxo-1 in dioxane (2 mL) , 2,3,4-Tetrahydroisoquinolin-6-yl) acetate (32 mg, 0.057 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (48 mg, 0.23 mmol), Pd (Pt-Bu ₃ ) A mixture of ₂ (5.9 mg, 0.01 mmol) and Cs ₂ CO ₃ (55 mg, 0.17 mmol) was stirred at 90 ° C. for 15 minutes under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-10% MeOH in DCM). To give the title compound (27 mg, 79% yield). LC-MS (ESI): m / z (M + 1) = 595.22.

Step 9: (S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-2- (1- Methylpiperidin-4-yl) -3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl in EtOH (0.5 mL) and dioxane (1 mL) To a mixture of -2- (1-methylpiperidin-4-yl) -3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (27 mg, 0.045 mmol) was added LiOH (2.5 N, 0.18 mL, 0.45 mmol) was added. After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) gave the title compound (6 mg, 23% yield). LC-MS (ESI): m / z (M + 1) = 567.41. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.63 (d, J = 11.3 Hz, 1H), 4.93 (s, 1H), 4.59- 4.52 (m, 1H), 4.33-4.15 (m, 4H), 3.79-3.63 (m, 2H), 3.38-3.12 (m, 4H), 2.74-2.35 (m, 10H), 2.17-2.10 (m, 2H ), 1.97 (s, 3H), 1.76-1.67 (m, 5H), 1.08 (s, 9H) (no acid protons were observed).

[Example 113]
((S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-3-oxo-2- ( (Tetrahydro-2H-pyran-4-yl) methyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: N-((tetrahydro-2H-pyran-4-yl) methyl) but-2-yn-1-amine

To (tetrahydro-2H-pyran-4-yl) methanamine (5 g, 43.5 mmol) was slowly added 1-bromobut-2-yne (1.0 g, 7.52 mmol) at 0 ° C. After stirring at 0 ° C. for 30 minutes, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-10% MeOH in DCM). The title compound (1.1 g, 50% yield) was obtained as a colorless oil. LC-MS (ESI): m / z (M + 1) = 168.12.

Step 2: N- (but-2-yn-1-yl) -N-((tetrahydro-2H-pyran-4-yl) methyl) pent-3-inamide

N-((Tetrahydro-2H-pyran-4-yl) methyl) but-2-yn-1-amine (500 mg, 3.0 mmol), penta-3-ynoic acid (441 mg, 4.5 mmol) in THF (10 mL) To the mixture was added EDCI (860 mg, 4.5 mmol) and TEA (606 mg, 6.0 mmol). After stirring at room temperature for 3 hours, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-10% MeOH in DCM). To give the title compound (620 mg, 85% yield) as a colorless oil. LC-MS (ESI): m / z (M + 1) = 248.49.

Step 3: Ethyl (S) -2- (5,8-dimethyl-3-oxo-2-((tetrahydro-2H-pyran-4-yl) methyl) -7- (trimethylsilyl) -1,2,3, 4-Tetrahydroisoquinolin-6-yl) -2-hydroxyacetate

A mixture of Rh (cod) ₂ BF ₄ (130 mg, 0.32 mmol) and BINAP (200 mg, 0.32 mmol) in DCM (10 mL) was stirred at room temperature for 6 hours under H ₂ atmosphere. After concentration, the resulting mixture was dissolved in DCE (10 mL) and ethyl (S) -2-hydroxy-4- (trimethylsilyl) but-3-inoate (648 mg, 3.2 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 80 ° C. and N- (but-2-yn-1-yl) -N-((tetrahydro-2H-pyran-4-yl) methyl) pent-3-inamide ( 400 mg, 1.6 mmol) was added as a DCE solution (10 mL) over 3 hours. After stirring at 80 ° C. for 30 minutes, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (200 mg, 27% yield) was obtained. LC-MS (ESI): m / z (M + 1) = 448.12.

Step 4: Ethyl (S) -2-hydroxy-2- (7-iodo-5,8-dimethyl-3-oxo-2-((tetrahydro-2H-pyran-4-yl) methyl) -1,2, 3,4-Tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (5,8-dimethyl-3-oxo-2-((tetrahydro-2H-pyran-4-yl) methyl) -7- (trimethylsilyl) -1,2,3,4-tetrahydro To a solution of isoquinolin-6-yl) -2-hydroxyacetate (40 mg, 0.09 mmol) in DCM (1 mL) at 0 ° C. was added ICl (2.5 M solution in DCM, 0.03 mL, 0.09 mmol). After stirring at 0 ° C. for 10 minutes, the resulting mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a crude product that was used in the next step without further purification. LC-MS (ESI): m / z (M + 1) = 502.24.

Step 5: Ethyl (S) -2- (tert-butoxy) -2- (7-iodo-5,8-dimethyl-3-oxo-2-((tetrahydro-2H-pyran-4-yl) methyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2-hydroxy-2- (7-iodo-5,8-dimethyl-3-oxo-2-((tetrahydro-2H-pyran-4-yl) methyl) -1,2,3,4 To a solution of -tetrahydroisoquinolin-6-yl) acetate (crude product from the previous step, 0.09 mmol) in t-BuOAc (1 mL) was added HClO ₄ (9 mg, 0.09 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-100% EtOAc in PE). To give the title compound (30 mg, 60% yield over 2 steps). LC-MS (ESI): m / z (M + 1) = 558.25.

Step 6: (S) -Ethyl 2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-3-oxo- 2-((Tetrahydro-2H-pyran-4-yl) methyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (tert-butoxy) -2- (7-iodo-5,8-dimethyl-3-oxo-2-((tetrahydro-2H-pyran-4-yl) in dioxane (2 mL) (Methyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (30 mg, 0.054 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (45 mg, 0.22 mmol), Pd A mixture of (Pt-Bu ₃ ) ₂ (5.6 mg, 0.011 mmol) and Cs ₂ CO ₃ (53 mg, 0.16 mmol) was stirred at 90 ° C. for 15 minutes under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (25 mg, 91% yield). LC-MS (ESI): m / z (M + 1) = 596.40.

Step 7: ((S) -2- (tert-butoxy) -2-((R) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl-3-oxo- 2-((Tetrahydro-2H-pyran-4-yl) methyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (7- (8-fluoro-5-methylchroman-6-yl) -5,8-dimethyl in EtOH (0.5 mL) and dioxane (1 mL) A mixture of -3-oxo-2-((tetrahydro-2H-pyran-4-yl) methyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (27 mg, 0.045 mmol) was added to LiOH ( 2.5N, 0.18 mL, 0.45 mmol) was added. After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) afforded the title compound (12 mg, 47% yield). LC-MS (ESI):. M / z (M + 1) = 568.32 1 H NMR (400 MHz, CDCl 3) δ 9.56 (br, 1H), 6.69 (d, J = 11.3 Hz, 1H), 5.07 ( s, 1H), 4.45 (s, 2H), 4.27 (dd, J = 10.2, 4.4 Hz, 2H), 3.98 (d, J = 11.3 Hz, 2H), 3.62 (s, 2H), 3.53-3.33 (m , 4H), 2.75-2.60 (m, 2H), 2.29 (s, 3H), 2.15-2.02 (m, 3H), 1.87-1.76 (m, 6H), 1.63-1.57 (m, 2H), 1.47-1.37 (m, 2H), 1.12 (s, 9H).

[Example 114]
(S) -2- (tert-butoxy) -2-((R) -2- (4,4-difluorocyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8 -Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: tert-butylbut-2-yn-1-yl (4,4-difluorocyclohexyl) carbamate

To a solution of tert-butyl (4,4-difluorocyclohexyl) carbamate (1.0 g, 4.25 mmol) in DMF (10 mL) was added NaH (60%, 255 mg, 6.38 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 30 minutes before 1-bromobut-2-yne (622 mg, 4.67 mmol) was introduced. After stirring at room temperature overnight, the resulting mixture was quenched with saturated aqueous NH 4 Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 20% EtOAc in PE) To give the title compound (1.0 g, 81% yield). LC-MS (ESI): m / z (M + 1) = 288.24.

Step 2: N- (but-2-yn-1-yl) -4,4-difluorocyclohexane-1-amine

  To a solution of tert-butylbut-2-in-1-yl (4,4-difluorocyclohexyl) carbamate (500 mg, 1.74 mmol) in DCM (5 mL) was added 4N HCl in dioxane (5 mL). After stirring at room temperature for 1 hour, the resulting mixture was concentrated to give the title compound (crude, as HCl salt), which was used in the next step without further purification. LC-MS (ESI): m / z (M + 1) = 188.65.

Step 3: N- (but-2-yn-1-yl) -N- (4,4-difluorocyclohexyl) pent-3-ynamide

Of N- (but-2-yn-1-yl) -4,4-difluorocyclohexane-1-amine (250 mg, 1.34 mmol), penta-3-ynoic acid (196 mg, 2.0 mmol) in THF (10 mL). To the mixture was added EDCI (382 mg, 2.0 mmol) and TEA (270 mg, 2.68 mmol). After stirring at room temperature for 3 hours, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 20% EtOAc in PE) To give the title compound (360 mg, 78% yield) as a colorless oil. LC-MS (ESI): m / z (M + 1) = 268.32.

Step 4: Ethyl (S) -2- (2- (4,4-difluorocyclohexyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinoline-6 -Il) -2-Hydroxyacetate

A mixture of Rh (cod) ₂ BF ₄ (85 mg, 0.21 mmol) and BINAP (131 mg, 0.21 mmol) in DCM (5 mL) was stirred under H ₂ atmosphere for 6 hours at room temperature. After concentration, the resulting mixture was dissolved in DCE (10 mL) and ethyl (S) -2-hydroxy-4- (trimethylsilyl) but-3-inoate (420 mg, 2.1 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 80 ° C. and N- (but-2-yn-1-yl) -N- (4,4-difluorocyclohexyl) pent-3-inamide (280 mg, 1.05 mmol) was added. DCE solution (10 mL) was added over 3 hours. After stirring at 80 ° C. for 30 minutes, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (210 mg 24% yield). LC-MS (ESI): m / z (M + 1) = 468.35.

Step 5: Ethyl (S) -2- (2- (4,4-difluorocyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl ) -2-Hydroxyacetate

Ethyl (S) -2- (2- (4,4-difluorocyclohexyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) To a solution of 2-hydroxyacetate (120 mg, 0.26 mmol) in DCM (2 mL) was added ICl (2.5 M solution in DCM, 0.1 mL, 0.25 mmol) at 0 ° C. After stirring at 0 ° C. for 10 minutes, the resulting mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a crude product that was used in the next step without further purification.

Step 6: Ethyl (S) -2- (tert-butoxy) -2- (2- (4,4-difluorocyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3, 4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (2- (4,4-difluorocyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) -2 To a solution of -hydroxyacetate (crude product from the previous step, 0.26 mmol) in t-BuOAc (2 mL) was added HClO ₄ (26 mg, 0.26 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (80 mg, 53% yield over 2 steps). LC-MS (ESI): m / z (M + 1) = 578.18.

Step 7: (S) -Ethyl 2- (tert-butoxy) -2-((R) -2- (4,4-difluorocyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (tert-butoxy) -2- (2- (4,4-difluorocyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2 in DMF (1 mL) , 3,4-Tetrahydroisoquinolin-6-yl) acetate (40 mg, 0.069 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (23 mg, 0.11 mmol), Pd ₂ (dba) ₃ ( A mixture of 13 mg, 0.014 mmol), MePhos (5.1 mg, 0.014) and K ₃ PO ₄ (44 mg, 0.208 mmol) was stirred at 80 ° C. overnight under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (20 mg, 48% yield). LC-MS (ESI): m / z (M + 1) = 616.28.

Step 8: (S) -2- (tert-butoxy) -2-((R) -2- (4,4-difluorocyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl)- 5,8-Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (2- (4,4-difluorocyclohexyl) -7- (8-fluoro-5-methyl) in EtOH (0.25 mL) and dioxane (0.5 mL) Chroman-6-yl) -5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (20 mg, 0.0322 mmol) was added to LiOH (2.5 N, 0.13 mL). 0.32 mmol) was added. After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) gave the title compound (9.6 mg, 51% yield). LC-MS (ESI): m / z (M + 1) = 588.51. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.54 (br, 1H), 6.68 (d, J = 11.3 Hz, 1H), 5.08 ( s, 1H), 4.78 (t, J = 11.4 Hz, 1H), 4.40-4.18 (m, 4H), 3.71-3.54 (m, 2H), 2.77-2.61 (m, 2H), 2.36-2.07 (m, 7H), 2.04-1.70 (m, 12H), 1.12 (s, 9H).

[Example 115]
((S) -2- (tert-butoxy) -2-((R) -2- (1- (tert-butoxycarbonyl) piperidin-4-yl) -7- (8-fluoro-5-methylchroman- 6-yl) -5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: tert-butyl (S) -4- (6- (1- (tert-butoxy) -2-ethoxy-2-oxoethyl) -7-iodo-5,8-dimethyl-3-oxo-3,4 -Dihydroisoquinolin-2 (1H) -yl) piperidine-1-carboxylate

Ethyl (S) -2- (tert-butoxy) -2- (7-iodo-5,8-dimethyl-3-oxo-2- (piperidin-4-yl) -1,2, in DCM (2 mL) A mixture of 3,4-tetrahydroisoquinolin-6-yl) acetate (20 mg, 0.04 mmol), Boc ₂ O (8 mg, 0.06 mmol) and TEA (8 mg, 0.08 mmol) was stirred at room temperature overnight. The resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (15 mg, 60% yield). LC-MS (ESI): m / z (M + 1) = 643.33.

Step 2: tert-butyl 4-((R) -6-((S) -1- (tert-butoxy) -2-ethoxy-2-oxoethyl) -7- (8-fluoro-5-methylchroman-6 -Yl) -5,8-dimethyl-3-oxo-3,4-dihydroisoquinolin-2 (1H) -yl) piperidine-1-carboxylate

Tert-Butyl (S) -4- (6- (1- (tert-butoxy) -2-ethoxy-2-oxoethyl) -7-iodo-5,8-dimethyl-3-oxo- in dioxane (1 mL) 3,4-dihydroisoquinolin-2 (1H) -yl) piperidine-1-carboxylate (15 mg, 0.023 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (20 mg, 0.092 mmol), A mixture of Pd (Pt-Bu ₃ ) ₂ (2.4 mg, 0.0046 mmol) and Cs ₂ CO ₃ (22.5 mg, 0.069 mmol) was stirred at 90 ° C. for 15 minutes under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (10 mg, 63% yield). LC-MS (ESI): m / z (M + 1) = 681.40.

Step 3: ((S) -2- (tert-butoxy) -2-((R) -2- (1- (tert-butoxycarbonyl) piperidin-4-yl) -7- (8-fluoro-5- Methylchroman-6-yl) -5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Tert-Butyl 4- (6-((S) -1- (tert-butoxy) -2-ethoxy-2-oxoethyl) -7- (8-fluoro-) in EtOH (0.25 mL) and dioxane (0.5 mL) To a mixture of 5-methylchroman-6-yl) -5,8-dimethyl-3-oxo-3,4-dihydroisoquinolin-2 (1H) -yl) piperidine-1-carboxylate (10 mg, 0.015 mmol), LiOH (2.5N, 0.06 mL, 0.15 mmol) was added. After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) afforded the title compound (5.6 mg, 59% yield). LC-MS (ESI): m / z (M + 1) = 653.43. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.68 (br, 1H), 6.69 (d, J = 11.3 Hz, 1H), 5.08 ( s, 1H), 4.86-4.73 (m, 1H), 4.56-3.98 (m, 6H), 3.64 (s, 2H), 2.94-2.77 (m, 2H), 2.76-2.57 (m, 2H), 2.29 ( s, 3H), 2.18-2.06 (m, 2H), 1.91-1.59 (m, 10H), 1.47 (s, 9H), 1.12 (s, 9H).

[Example 116]
(2S) -2- (tert-butoxy) -2-((7R) -2- (2,2-dimethylcyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8 -Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: N- (but-2-yn-1-yl) -2,2-dimethylcyclohexane-1-amine

To a solution of tert-butyl (2,2-dimethylcyclohexyl) carbamate (2.0 g, 8.8 mmol) in DMF (20 mL) was added NaH (60%, 528 mg, 13.2 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 30 minutes before 1-bromobut-2-yne (1.29 g, 9.7 mmol) was introduced. After stirring at room temperature overnight, the resulting mixture was quenched with saturated aqueous NH 4 Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 20% EtOAc in PE) To give the title compound (2.0 g, 81% yield). LC-MS (ESI): m / z (M + 1) = 280.34. To a solution of tert-butylbut-2-yn-1-yl (2,2-dimethylcyclohexyl) carbamate (500 mg, 1.79 mmol) in DCM (10 mL) was added 4N HCl in dioxane (5 mL). After stirring at room temperature for 1 hour, the resulting mixture was concentrated to give the title compound (crude, as HCl salt), which was used in the next step without further purification. LC-MS (ESI): m / z (M + 1) = 180.40.

Step 2: N- (but-2-yn-1-yl) -N- (2,2-dimethylcyclohexyl) pent-3-inamide

Of N- (but-2-yn-1-yl) -2,2-dimethylcyclohexane-1-amine (500 mg, 2.8 mmol), penta-3-ynoic acid (411 mg, 4.2 mmol) in THF (10 mL). To the mixture was added EDCI (802 mg, 4.2 mmol) and TEA (566 mg, 5.6 mmol). After stirring at room temperature for 3 hours, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (250 mg, 34% yield) as a colorless oil. LC-MS (ESI): m / z (M + 1) = 260.36.

Step 3: Ethyl (2S) -2- (2- (2,2-dimethylcyclohexyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinoline-6 -Il) -2-Hydroxyacetate

A mixture of Rh (cod) ₂ BF ₄ (77 mg, 0.19 mmol) and BINAP (118 mg, 0.19 mmol) in DCM (5 mL) was stirred under H ₂ atmosphere for 6 hours at room temperature. After concentration, the resulting mixture was dissolved in DCE (10 mL) and ethyl (S) -2-hydroxy-4- (trimethylsilyl) but-3-inoate (386 mg, 1.93 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 80 ° C. and N- (but-2-yn-1-yl) -N- (2,2-dimethylcyclohexyl) pent-3-inamide (250 mg, 0.96 mmol) was added. DCE solution (10 mL) was added over 3 hours. After stirring at 80 ° C. for 30 minutes, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (170 mg 39% yield). LC-MS (ESI): m / z (M + 1) = 460.42.

Step 4: Ethyl (2S) -2- (2- (2,2-dimethylcyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl ) -2-Hydroxyacetate

Ethyl (2S) -2- (2- (2,2-dimethylcyclohexyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) To a solution of -2-hydroxyacetate (170 mg, 0.37 mmol) in DCM (4 mL) at 0 ° C. was added ICl (2.5 M solution in DCM, 0.15 mL, 0.37 mmol). After stirring at 0 ° C. for 10 minutes, the resulting mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a crude product that was used in the next step without further purification.

Step 6: Ethyl (2S) -2- (tert-butoxy) -2- (2- (2,2-dimethylcyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3, 4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (2S) -2- (2- (2,2-dimethylcyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) -2 To a solution of -hydroxyacetate (crude product from the previous step, 0.37 mmol) in t-BuOAc (2 mL) was added HClO ₄ (37 mg, 0.37 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (20 mg, 10% yield over 2 steps). LC-MS (ESI): m / z (M + 1) = 570.37.

Step 7: (2S) -Ethyl 2- (tert-butoxy) -2-((7R) -2- (2,2-dimethylcyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (2S) -2- (tert-butoxy) -2- (2- (2,2-dimethylcyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2 in dioxane (2 mL) , 3,4-Tetrahydroisoquinolin-6-yl) acetate (20 mg, 0.035 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (30 mg, 0.141 mmol), Pd (Pt-Bu ₃ ) A mixture of ₂ (3.6 mg, 0.007 mmol) and Cs ₂ CO ₃ (36 mg, 0.11 mmol) was stirred at 90 ° C. for 15 min under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 40% EtOAc in PE) To give the title compound (18 mg, 86% yield). LC-MS (ESI): m / z (M + 1) = 608.90.

Step 8: (2S) -2- (tert-butoxy) -2-((7R) -2- (2,2-dimethylcyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl)- 5,8-Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (2- (2,2-dimethylcyclohexyl) -7- (8-fluoro-5-methyl) in EtOH (0.5 mL) and dioxane (1.0 mL) Chroman-6-yl) -5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (18 mg, 0.029 mmol) was added to LiOH (2.5 N, 0.12 mL). 0.3 mmol) was added. After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) gave the title compound (8 mg, 47% yield). LC-MS (ESI): m / z (M + 1) = 580.45. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.54 (br, 1H), 6.69 (d, J = 11.3 Hz, 1H), 5.09 ( s, 1H), 4.57-4.46 (m, 1H), 4.44-4.15 (m, 4H), 3.74-3.51 (m, 2H), 2.78-2.58 (m, 2H), 2.32 (s, 3H), 2.20- 2.06 (m, 2H), 1.87-1.41 (m, 14H), 1.26-0.78 (m, 15H).

[Example 117]
((2S) -2- (tert-butoxy) -2-((7R) -2- (3,3-difluorocyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl) -5, 8-Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: tert-butyl (3,3-difluorocyclohexyl) carbamate

A mixture of 3,3-difluorocyclohexane-1-amine (1.3 g, 9.6 mmol), Boc ₂ O (4.2 g, 19.2 mmol) and TEA (1.95 g, 19.2 mmol) in THF (20 mL) was stirred at room temperature. Stir overnight. The resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 20% EtOAc in PE) To give the title compound (1.4 g, 62% yield) as a yellow solid. LC-MS (ESI): m / z (M + 1) = 236.24.

Step 2: tert-Butylbut-2-yn-1-yl (3,3-difluorocyclohexyl) carbamate

To a solution of tert-butyl (3,3-difluorocyclohexyl) carbamate (1.3 g, 5.5 mmol) in DMF (20 mL) was added NaH (60%, 332 mg, 8.29 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 30 minutes before 1-bromobut-2-yne (808 mg, 6.08 mmol) was introduced. After stirring at room temperature overnight, the resulting mixture was quenched with saturated aqueous NH 4 Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 20% EtOAc in PE) To give the title compound (1.5 g, 94% yield). LC-MS (ESI): m / z (M + 1) = 288.31.

Step 3: N- (but-2-yn-1-yl) -3,3-difluorocyclohexane-1-amine

A mixture of tert-butylbut-2-in-1-yl (3,3-difluorocyclohexyl) carbamate (1.5 g, 5.22 mmol) in 4N HCl (15 mL) in dioxane and DCM (20 mL) was stirred at room temperature for 2 hours. Stir. The resulting mixture was concentrated under reduced pressure and the residue was diluted with DCM, washed with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (936 mg, (96% yield) was obtained and used in the next step without further purification. LC-MS (ESI): m / z (M + 1) = 188.50.

Step 4: N- (but-2-yn-1-yl) -N- (3,3-difluorocyclohexyl) pent-3-inamide

Of N- (but-2-yn-1-yl) -3,3-difluorocyclohexane-1-amine (500 mg, 2.67 mmol), penta-3-ynoic acid (393 mg, 4.0 mmol) in THF (10 mL). To the mixture was added EDCI (764 mg, 4.0 mmol) and TEA (536 mg, 5.3 mmol). After stirring at room temperature for 3 hours, the resulting mixture was partitioned between EtOAc and H ₂ O. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 30% EtOAc in PE) To give the title compound (500 mg, 70% yield) as a colorless oil. LC-MS (ESI): m / z (M + 1) = 268.56.

Step 5: Ethyl (2S) -2- (2- (3,3-difluorocyclohexyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinoline-6 -Il) -2-Hydroxyacetate

A mixture of Rh (cod) ₂ BF ₄ (150 mg, 0.37 mmol) and BINAP (230 mg, 0.37 mmol) in DCM (10 mL) was stirred at room temperature for 6 hours under H ₂ atmosphere. After concentration, the resulting mixture was dissolved in DCE (10 mL) and ethyl (S) -2-hydroxy-4- (trimethylsilyl) but-3-inoate (748 mg, 3.74 mmol) was introduced. In a sealed tube, the reaction mixture was heated to 80 ° C. and N- (but-2-yn-1-yl) -N- (3,3-difluorocyclohexyl) pent-3-inamide (500 mg, 1.87 mmol) was added. DCE solution (10 mL) was added over 3 hours. After stirring at 80 ° C. for 30 minutes, the resulting mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (300 mg , 34% yield). LC-MS (ESI): m / z (M + 1) = 468.32.

Step 6: Ethyl (2S) -2- (2- (3,3-difluorocyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl ) -2-Hydroxyacetate

Ethyl (2S) -2- (2- (3,3-difluorocyclohexyl) -5,8-dimethyl-3-oxo-7- (trimethylsilyl) -1,2,3,4-tetrahydroisoquinolin-6-yl) To a solution of 2-hydroxyacetate (100 mg, 0.21 mmol) in DCM (2 mL) was added ICl (2.5 M solution in DCM, 0.13 mL, 0.32 mmol) at 0 ° C. After stirring at 0 ° C. for 10 minutes, the resulting mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound as a crude product that was used in the next step without further purification.

Step 7: Ethyl (2S) -2- (tert-butoxy) -2- (2- (3,3-difluorocyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3, 4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (2S) -2- (2- (3,3-difluorocyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) -2 To a solution of -hydroxyacetate (crude product from the previous step, 0.21 mmol) in t-BuOAc (2 mL) was added HClO ₄ (32 mg, 0.32 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (40 mg, 33% yield over 2 steps). LC-MS (ESI): m / z (M + 1) = 578.66.

Step 8: (2S) -Ethyl 2- (tert-butoxy) -2-((7R) -2- (3,3-difluorocyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl) -5,8-Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (2S) -2- (tert-butoxy) -2- (2- (3,3-difluorocyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2 in dioxane (2 mL) , 3,4-Tetrahydroisoquinolin-6-yl) acetate (40 mg, 0.069 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (58 mg, 0.277 mmol), Pd (Pt-Bu ₃ ) A mixture of ₂ (7.1 mg, 0.014 mmol) and Cs ₂ CO ₃ (68 mg, 0.21 mmol) was stirred at 90 ° C. for 15 minutes under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (12 mg, 28% yield). LC-MS (ESI): m / z (M + 1) = 616.33.

Step 9: (2S) -2- (tert-butoxy) -2-((7R) -2- (3,3-difluorocyclohexyl) -7- (8-fluoro-5-methylchroman-6-yl)- 5,8-Dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (2- (3,3-difluorocyclohexyl) -7- (8-fluoro-5-methyl) in EtOH (0.5 mL) and dioxane (1.0 mL) Chroman-6-yl) -5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (10 mg, 0.016 mmol) was added to LiOH (2.5 N, 0.06 mL). 0.15 mmol) was added. After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) afforded the title compound (4.6 mg, 48% yield). LC-MS (ESI): m / z (M + 1) = 588.26. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.67 (br, 1H), 6.68 (d, J = 11.3 Hz, 1H), 5.07 ( s, 1H), 4.75-4.65 (m, 1H), 4.41-4.30 (m, 2H), 4.29-4.25 (m, 2H), 3.68-3.57 (m, 2H), 2.76-2.64 (m, 2H), 2.29 (s, 3H), 2.26-2.21 (m, 1H), 2.19-2.07 (m, 4H), 1.91-1.79 (m, 8H), 1.73-1.62 (m, 3H), 1.12 (s, 9H).

[Example 118]
((S) -2- (tert-butoxy) -2-((R) -7- (8-chloro-5-methylchroman-6-yl) -2-cyclohexyl-5,8-dimethyl-3-oxo -1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: (S) -Ethyl 2- (tert-butoxy) -2-((R) -7- (8-chloro-5-methylchroman-6-yl) -2-cyclohexyl-5,8-dimethyl- 3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (2S) -2- (tert-butoxy) -2- (2- (3,3-difluorocyclohexyl) -7-iodo-5,8-dimethyl-3-oxo-1,2 in dioxane (2 mL) , 3,4-Tetrahydroisoquinolin-6-yl) acetate (42 mg, 0.078 mmol), (8-fluoro-5-methylchroman-6-yl) boronic acid (96 mg, 0.32 mmol), Pd (Pt-Bu ₃ ) A mixture of ₂ (8 mg, 0.0155 mmol) and Cs ₂ CO ₃ (76 mg, 0.233 mmol) was stirred at 90 ° C. for 15 minutes under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (30 mg, 67% yield). LC-MS (ESI): m / z (M / M + 2) = 596.53 / 598.50.

Step 2: (S) -2- (tert-butoxy) -2-((R) -7- (8-chloro-5-methylchroman-6-yl) -2-cyclohexyl-5,8-dimethyl-3 -Oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (7- (8-chloro-5-methylchroman-6-yl) -2-cyclohexyl- in EtOH (0.5 mL) and dioxane (1.0 mL) To a mixture of 5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (30 mg, 0.05 mmol) was added LiOH (2.5 N, 0.2 mL, 0.5 mmol). . After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) gave the title compound (9.6 mg, 34% yield). LC-MS (ESI): m / z (M / M + 2) = 568.69 / 570.70. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.74 (br, 1H), 6.96 (s, 1H), 5.04 (s , 1H), 4.65-4.57 (m, 1H), 4.38-4.27 (m, 4H), 3.67-3.56 (m, 2H), 2.77-2.64 (m, 2H), 2.29 (s, 3H), 2.15-2.08 (m, 2H), 1.90-1.81 (m, 8H), 1.79-1.66 (m, 4H), 1.54-1.43 (m, 4H), 1.12 (s, 9H).

[Example 119]
(S) -2- (tert-butoxy) -2-((R) -2-cyclohexyl-5,8-dimethyl-7- (5-methyl-3,4-dihydro-2H-benzo [b] [1 , 4] Oxazin-6-yl) -3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Step 1: Ethyl (2S) -2- (tert-butoxy) -2-((R) -2-cyclohexyl-5,8-dimethyl-7- (5-methyl-3,4-dihydro-2H-benzo [ b] [1,4] oxazin-6-yl) -3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (tert-butoxy) -2- (2-cyclohexyl-7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinoline in DMF (2 mL) -6-yl) acetate (20 mg, 0.037 mmol), 5-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4-dihydro- 2H-benzo [b] [1,4] oxazine (20 mg, 0.074 mmol), Pd ₂ (dba) ₃ (6.4 mg, 0.007 mmol), MePhos (2.5 mg, 0.007 mmol) and K ₃ PO ₄ (23 mg, 0.111 mmol) was stirred at 90 ° C. for 15 minutes under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (9 mg, 45% yield). LC-MS (ESI): m / z (M + 1) = 563.53.

Step 2: (S) -2- (tert-butoxy) -2-((R) -2-cyclohexyl-5,8-dimethyl-7- (5-methyl-3,4-dihydro-2H-benzo [b ] [1,4] oxazin-6-yl) -3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (2-cyclohexyl-5,8-dimethyl-7- (5-methyl-3,4-) in EtOH (0.25 mL) and dioxane (0.5 mL) To a mixture of dihydro-2H-benzo [b] [1,4] oxazin-6-yl) -3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (9 mg, 0.016 mmol), LiOH (2.5N, 0.06 mL, 0.15 mmol) was added. After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) afforded the title compound (3.5 mg, 41% yield). LC-MS (ESI): m / z (M + 1) = 535.65. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.62 (br, 1H), 6.71 (d, J = 8.2 Hz, 1H), 6.42 ( d, J = 8.1 Hz, 1H), 5.40-5.28 (m, 1H), 5.14 (s, 1H), 4.65-4.58 (m, 1H), 4.40-4.25 (m, 4H), 3.66-3.49 (m, 4H), 2.26 (s, 3H), 1.88-1.76 (m, 8H), 1.74-1.68 (m, 2H), 1.58-1.48 (m, 6H), 1.10 (s, 9H).

[Example 120]
(S) -2- (tert-butoxy) -2-((R) -2-cyclohexyl-5,8-dimethyl-7- (5-methylchroman-6-yl) -3-oxo-1,2, 3,4-Tetrahydroisoquinolin-6-yl) acetic acid

Step 1: Ethyl (2S) -2- (tert-butoxy) -2- (2-cyclohexyl-5,8-dimethyl-7- (5-methylchroman-6-yl) -3-oxo-1,2, 3,4-Tetrahydroisoquinolin-6-yl) acetate

Ethyl (S) -2- (tert-butoxy) -2- (2-cyclohexyl-7-iodo-5,8-dimethyl-3-oxo-1,2,3,4-tetrahydroisoquinoline in DMF (2 mL) -6-yl) acetate (42 mg, 0.08 mmol), 4,4,5,5-tetramethyl-2- (5-methylchroman-6-yl) -1,3,2-dioxaborolane (44 mg, 0.16 mmol) , Pd ₂ (dba) ₃ (15 mg, 0.016 mmol), MePhos (6 mg, 0.016 mmol) and K ₃ PO ₄ (51 mg, 0.24 mmol) were stirred at 90 ° C. for 15 minutes under N ₂ atmosphere. The resulting mixture was partitioned between H ₂ O and EtOAc. The organic layer was washed with brine, dried over Na ₂ SO _4, filtered, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) To give the title compound (20 mg, 44% yield). LC-MS (ESI): m / z (M + 1) = 562.45.

Step 2: (S) -2- (tert-butoxy) -2-((R) -2-cyclohexyl-5,8-dimethyl-7- (5-methylchroman-6-yl) -3-oxo-1 , 2,3,4-Tetrahydroisoquinolin-6-yl) acetic acid

Ethyl (2S) -2- (tert-butoxy) -2- (2-cyclohexyl-5,8-dimethyl-7- (5-methylchroman-6-yl) in EtOH (0.5 mL) and dioxane (1.0 mL) To a mixture of) -3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl) acetate (20 mg, 0.036 mmol) was added LiOH (2.5 N, 0.14 mL, 0.36 mmol). After stirring at 100 ° C. overnight, the resulting mixture was acidified with 1N HCl to pH 3-4 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was HPLC (C18, 0-100% in H ₂ O with 0.1% formic acid. Purification by MeCN) afforded the title compound (7 mg, 37% yield). LC-MS (ESI): m / z (M + 1) = 534.56. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.67 (br, 1H), 6.82 (d, J = 7.9 Hz, 1H), 6.71 ( d, J = 8.3 Hz, 1H), 5.12 (s, 1H), 4.66-4.57 (m, 1H), 4.40-4.28 (m, 2H), 4.25-4.12 (m, 2H), 3.68-3.56 (m, 2H), 2.75-2.60 (m, 2H), 2.28 (s, 3H), 2.14-2.04 (m, 2H), 1.90 (s, 3H), 1.82 (s, 3H), 1.79-1.67 (m, 3H) , 1.62-1.44 (m, 7H), 1.10 (s, 9H).

[Example 121]
2- (2-Benzyl-5,8-dimethyl-1-oxo-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert-butoxy) acetic acid

Step 1: penta-3-in-1-yl 4-methylbenzenesulfonate

A solution of penta-3-in-1-ol (4 g, 47.6 mmol) in ice-cold dichloromethane (DCM) (90 ml) was treated with Et3N (9.94 ml, 71.3 mmol), pTsCl (9.07 g, 47.6 mmol), then And stirred at room temperature for 1 day. The reaction was diluted with water, extracted with DCM, washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound (11.31 g, 47.5 mmol, 100% yield) as a pale yellow liquid. Obtained. ¹ H NMR (400MHz, chloroform-d) δ ppm 7.81 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.06 (t, J = 7.2 Hz, 2H), 2.54- 2.42 (m, 5H), 1.72 (t, J = 2.4 Hz, 3H); LCMS (m / z) ES ⁺ = 239 (M + 1) (low intensity).

Step 2: N-benzylpent-3-in-1-amine

A solution of penta-3-in-1-yl 4-methylbenzenesulfonate (4.5 g, 18.88 mmol) in acetonitrile (45 mL) is treated with benzylamine (8.25 mL, 76 mmol) in an oil bath at 90 ° C. in a sealed flask. Heated in. After 2.5 hours, the reaction was cooled to room temperature overnight. The suspension was diluted with Et2O, filtered and the filtrate was concentrated. The residue was diluted with saturated NaHCO3, extracted with Et2O, washed with brine, dried over Na2SO4, filtered and concentrated to give 5.3684 g of a brown liquid. The residue was diluted with Et2 O, washed with saturated NaHCO _3, brine, dried over Na2SO4, filtered, and concentrated to give the title compound (3.0111g, 17.38mmol, 92% yield) as a yellow liquid . ¹ H NMR (400MHz, chloroform-d) δ ppm 7.34 (d, J = 4.8 Hz, 4H), 7.29-7.21 (m, 1H), 3.83 (s, 2H), 2.76 (t, J = 6.5 Hz, 2H ), 2.40-2.30 (m, 2H), 1.79 (t, J = 2.5 Hz, 3H).

Step 3: N-benzyl-N- (pent-3-yn-1-yl) but-2-ynamide

A solution of N-benzylpent-3-in-1-amine (3 g, 17.32 mmol) in dichloromethane (DCM) (55 mL) was treated with DCC (4.11 g, 19.91 mmol) and DMAP (0.212 g, 1.732 mmol), Cooled to 0 ° C. and then treated with a solution of but-2-ynoic acid (1.601 g, 19.05 mmol) in dichloromethane (DCM) (10 mL). The reaction was stirred at room temperature for 18 hours, filtered and the filtrate concentrated. Purification by column chromatography (0-70% EtOAc / hexanes) gave the title compound (3.4306 g, 14.34 mmol, 83% yield) as a pale yellow oil. NMR indicates an approximately 1: 1 mixture of rotamers. ¹ H NMR (400MHz, chloroform-d) δ ppm 7.44-7.18 (m, 5H), 4.90 (s, 1H), 4.69 (s, 1H), 3.61 (t, J = 7.3 Hz, 1H), 3.42 (t , J = 7.2 Hz, 1H), 2.38 (tddd, J = 2.4, 4.7, 7.2, 14.3 Hz, 2H), 2.03 (d, J = 17.3 Hz, 3H), 1.78 (td, J = 2.6, 5.4 Hz, 3H); LCMS (m / z) ES ⁺ = 240 (M + 1).

Step 4: 2-benzyl-6- (benzyldimethylsilyl) -5,8-dimethyl-3,4-dihydroisoquinolin-1 (2H) -one and 2-benzyl-7- (benzyldimethylsilyl) -5,8 -Dimethyl-3,4-dihydroisoquinolin-1 (2H) -one

A degassed solution of N-benzyl-N- (pent-3-yn-1-yl) but-2-inamide (2 g, 8.36 mmol) in benzene (83.6 mL) was added to benzyl (ethynyl) dimethylsilane (2.91 g, 16.71 mmol), [IrCl (cod)] 2 (0.561 g, 0.836 mmol), DPPE (0.666 g, 1.671 mmol) and stirred at room temperature for 18 hours. The reaction was bubbled with N2 and treated with additional benzyl (ethynyl) dimethylsilane (493 mg), IrCl (cod) dimer (186 mg), dppe (235 mg) and then stirred for 1 day. The reaction was concentrated and purified by column chromatography (0-35% EtOAc / hexanes) to give 2-benzyl-6- (benzyldimethylsilyl) -5,8-dimethyl-3,4-dihydroisoquinoline-1 ( 2H) -one and 2-benzyl-7- (benzyldimethylsilyl) -5,8-dimethyl-3,4-dihydroisoquinolin-1 (2H) -one 1: 1 mixture (2.1 g, 5.08 mmol, 60.7% Yield) was obtained as a brown oil. ¹ H NMR (400MHz, chloroform-d) δ ppm 7.40-7.28 (m, 5H), 7.25-7.16 (m, 3H), 7.11-7.05 (m, 1H), 6.99 (dd, J = 7.3, 12.5 Hz, 2H), 4.80 (d, J = 4.3 Hz, 2H), 3.44 (dt, J = 3.5, 6.3 Hz, 2H), 2.84 (s, 1.5H), 2.78 (td, J = 6.4, 16.6 Hz, 2H) , 2.70 (s, 1.5H), 2.42 (d, J = 14.6 Hz, 2H), 2.32-2.20 (m, 3H), 0.30 (d, J = 1.8 Hz, 6H); LCMS (m / z) ES ⁺ = 414 (M + 1).

Step 5: 2-Benzyl-6-hydroxy-5,8-dimethyl-3,4-dihydroisoquinolin-1 (2H) -one and 2-benzyl-7-hydroxy-5,8-dimethyl-3,4-dihydro Isoquinolin-1 (2H) -one

2-Benzyl-6- (benzyldimethylsilyl) -5,8-dimethyl-3,4-dihydroisoquinolin-1 (2H) -one and 2-benzyl-7- (benzyldimethylsilyl) -5,8-dimethyl- A solution of 3,4-dihydroisoquinolin-1 (2H) -one (2.1 g, 5.08 mmol) in 1: 1 ice-cold tetrahydrofuran (THF) (12 mL) (open to air) was added to TBAF (1M in THF). (20.32 mL, 20.32 mmol) was added dropwise and then stirred at room temperature for 20 minutes. The mixture was treated with methanol (37 mL), KHCO3 (1.017 g, 10.16 mmol), H2O2 (30%) (5.19 mL, 50.8 mmol) and stirred at room temperature for 1.5 hours. The mixture was diluted with saturated aqueous Na2S2O3, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. Purify by column chromatography (0-60% EtOAc / hexane) to give 2-benzyl-6-hydroxy-5,8-dimethyl-3,4-dihydroisoquinolin-1 (2H) -one and 2-benzyl-7 An approximately 1: 1 mixture (0.56 g, 1.990 mmol, 39.2% yield) of -hydroxy-5,8-dimethyl-3,4-dihydroisoquinolin-1 (2H) -one was obtained as a yellow solid. ¹ H NMR (400MHz, chloroform-d) δ ppm 7.40-7.28 (m, 5H), 6.85-6.50 (m, 1H), 5.48 (s, 0.5H), 4.95 (s, 0.5H), 4.84-4.73 ( m, 2H), 3.48-3.30 (m, 2H), 2.83-2.76 (m, 1H), 2.73-2.67 (m, 1H), 2.63 (d, J = 19.1 Hz, 3H), 2.21-2.09 (m, 3H); LCMS (m / z) ES ⁺ = 282 (M + 1).

Step 6: Ethyl 2- (2-benzyl-6-hydroxy-5,8-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-hydroxyacetate

  2-Benzyl-6-hydroxy-5,8-dimethyl-3,4-dihydroisoquinolin-1 (2H) -one and 2-benzyl-7-hydroxy-5,8-dimethyl-3,4-dihydroisoquinoline-1 A 1: 1 mixture of (2H) -one (0.56 g, 1.990 mmol) in ice-cold dichloromethane (DCM) (9 mL) was treated with TiCl4 (0.241 mL, 2.189 mmol). After stirring for 5 minutes, the reaction was treated with ethyl 2-oxoacetate (50% in toluene) (0.434 mL, 2.189 mmol) and stirred at room temperature for 2 hours. The reaction was treated with additional ethyl 2-oxoacetate (500 uL) and stirred at room temperature for 1.5 hours. Additional TiCl4 (100 uL) and ethyl 2-oxoacetate (500 uL) were added and stirred at room temperature for 18 hours. The reaction was quenched with cold 1N HCl, extracted with DCM, washed with brine, dried over Na 2 SO 4, filtered and concentrated. Purify by column chromatography (0-60% EtOAc / DCM) and extract the mixture with ethyl 2- (2-benzyl-6-hydroxy-5,8-dimethyl-1-oxo-1,2,3,4-tetrahydro Isoquinolin-7-yl) -2-hydroxyacetate (202 mg, 0.527 mmol, 26.5% yield) was obtained as a turbid oil.

Step 7: Ethyl 2- (2-benzyl-6-hydroxy-5,8-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert-butoxy) acetate

Mixture of ethyl 2- (2-benzyl-6-hydroxy-5,8-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl) -2-hydroxyacetate (200 mg, 0.522 mmol) Solution of tert-butyl acetate (5 mL, 37.0 mmol) was added dropwise with perchloric acid (0.179 mL, 2.086 mmol) and stirred at room temperature for 30 minutes. The mixture was quenched with 15% aqueous NaOH and saturated NaHCO 3, extracted with EtOAc, washed with brine, dried over Na 2 SO 4, filtered, concentrated, and crude ethyl 2- (2-benzyl-6-hydroxy-5 , 8-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert-butoxy) acetate (131.5 mg, 0.299 mmol, 57.4% yield) as a pale yellow oil Got as. LCMS (m / z) ES ⁺ = 440 (M + 1).

Step 8: Ethyl 2- (2-benzyl-5,8-dimethyl-1-oxo-6-(((trifluoromethyl) sulfonyl) oxy) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert-butoxy) acetate

Crude ethyl 2- (2-benzyl-6-hydroxy-5,8-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert-butoxy) acetate (131.5 mg , 0.299 mmol) in N, N-dimethylformamide (DMF) (2 mL) was treated with K2CO3 (49.1 mg, 0.3552 mmol), N-phenyl-bis (trifluoromethanesulfonimide) (127 mg, 0.3552 mmol), Stir at room temperature over the weekend. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried over Na 2 SO 4, filtered and concentrated. Purify by column chromatography (0-15% EtOAc / DCM) to give ethyl 2- (2-benzyl-5,8-dimethyl-1-oxo-6-(((trifluoromethyl) sulfonyl) oxy) -1 , 2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert-butoxy) acetate (52 mg, 0.091 mmol, 30.7% yield) was obtained. The structure was confirmed by NOE. ¹ H NMR (400MHz, chloroform-d) δ ppm 7.39-7.29 (m, 5H), 5.57 (s, 1H), 4.90-4.65 (m, 2H), 4.28-4.08 (m, 2H), 3.56-3.37 ( m, 2H), 2.81 (t, J = 6.3 Hz, 2H), 2.67 (s, 3H), 2.26 (s, 3H), 1.24-1.15 (m, 12H); LCMS (m / z) ES ⁺ = 572 (M + 1).

Step 9: Ethyl 2- (2-benzyl-5,8-dimethyl-1-oxo-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert- Butoxy) acetate

Ethyl 2- (2-benzyl-5,8-dimethyl-1-oxo-6-(((trifluoromethyl) sulfonyl) oxy) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2- A solution of (tert-butoxy) acetate (52 mg, 0.091 mmol) in 1,2-dimethoxyethane (DME) (2 mL) was added to p-tolylboronic acid (16.08 mg, 0.118 mmol), CsF (55.3 mg, 0.364 mmol) and Treated with a cycle (20.76 mg, 0.027 mmol). The reaction was bubbled with N 2 for 5 minutes and then irradiated with microwaves at 130 ° C. for 20 minutes. The reaction was diluted with saturated NaHCO3, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated, and crude ethyl 2- (2-benzyl-5,8-dimethyl-1-oxo). -6- (p-Tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert-butoxy) acetate (56.8 mg, 0.111 mmol, 122% yield) was obtained. LCMS (m / z) ES ⁺ = 514 (M + 1). The crude was used for the next step.

Step 10: 2- (2-Benzyl-5,8-dimethyl-1-oxo-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert-butoxy Acetic acid

Crude ethyl 2- (2-benzyl-5,8-dimethyl-1-oxo-6- (p-tolyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) -2- (tert-butoxy) A solution of acetate (56.8 mg, 0.111 mmol) in 1,4-dioxane (2 mL) was treated with 2M LiOH (0.455 mL, 0.910 mmol) and stirred at 80 ° C. for 11 hours. The reaction was treated with additional 2M LiOH (455 uL) and irradiated with microwaves at 120 ° C. for 40 minutes. The mixture was concentrated and purified by reverse phase HPLC (30-100% MeCN / H 2 O-0.1% TFA) to give the title compound (20.3 mg, 0.041 mmol, 45.0% yield) as a white solid. ¹ H NMR (400MHz, methanol-d ₄ ) δ ppm 7.42-7.33 (m, 4H), 7.32-7.24 (m, 4H), 7.10 (d, J = 7.5 Hz, 1H), 5.11 (s, 1H), 4.82-4.77 (m, 2H), 3.55-3.44 (m, 2H), 2.84 (s, 2H), 2.65 (s, 3H), 2.42 (s, 3H), 1.89 (s, 3H), 0.95 (s, 9H); LCMS (m / z) ES ⁺ = 486 (M + 1).

Anti-HIV activity
MT4 assay Antiviral HIV activity and cytotoxicity values for the compounds of the invention from Table 1 were measured in parallel in the HTLV-1 transformed cell line MT-4 based on previously described methods (Hazen et al., 2007, In vitro antiviral activity of the novel, tyrosyl-based human immunodeficiency virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV (Hazen `` In vitro antiviral activity of the novel, tyrosyl-based human immunodeficiency virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV '', Antimicrob.Agents Chemother. 2007, 51: 3147-3154; and Pauwels et al., `` Sensitive and rapid assay on MT-4 cells for the detection of antiviral compounds against the AIDS virus '', J. of Virological Methods 1987, 16: 171- 185).

Luciferase activity was measured after 96 hours by adding cell titer glo (Promega, Madison, Wis). The percentage inhibition of cytoprotection data was plotted against the no compound control. Under the same conditions, the cytotoxicity of the compounds was determined using a cell titer Glo ™ (Promega, Madison, Wis). IC ₅₀ was determined for each compound from a 10-point dose response curve using 3-4 fold serial dilutions spanning a> 1000 fold concentration range.

These values are plotted against the molar concentration of the compound using a standard 4-parameter logistic formula:
y = ((Vmax * x ^ n) / (K ^ n + x ^ n)) + Y2
(Where
Y2 = minimum yn = slope coefficient
Vmax = maximum yx = compound concentration [M]
K = EC ₅₀ ).

When tested in the MT4 assay, the compounds were found to have IC ₅₀ values listed in Table 1.

Claims (18)

Compounds of formula I:

(Where
Each Y is independently C═O, CH—R ⁶ or NLR ³ R ³ , provided that at least one Y must be CH—R ⁶ ;
X is O or CH ₂
R ¹ is C _1-6 alkyl, which alkyl may contain a cycloalkyl moiety,
W is a bond, —CH═CH—, —C≡C—, C _1-3 alkylene, —CH ₂ C (O) NH—, —NHC (O) —, —N (CH ₃ ) C (O) -, -N (CH ₃ ) C (O) CH _2- , -C (O)-, -CH ₂ (CO)-or -NHC (O) CH _2- , wherein each W is 1 or 2 Optionally substituted by two methyl groups,
R ² is H, C _1-6 alkyl, C _5-14 aryl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _3-9 heterocycle or C _5-9 heteroaryl, wherein Each R ² group is optionally substituted with 1 to 4 substituents selected from halo, C _1-6 alkyl, C _1-6 heteroalkyl or C _1-6 alkylene or C _1-6 heteroalkylene. The C _1-6 alkylene or C _1-6 heteroalkylene is the C _5-14 aryl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _3-9 heterocycle or C _5-9 heterocycle. Bonded to adjacent carbon atoms on the aryl to form a fused ring;
Each L is independently a _{bond, -CH 2 (CO) -,} - C 1~3 alkylene _{-, - SO 2 -, -} C (O) -, - C (S) -, - C (NH) -, -C (O) NH-, -C (O) NHCH _2- , -C (O) N-, -C (O) OCH _2- , -C (O) O-, -C (O) C (O)-, -SO ₂ -NH- or -CH ₂ C (O)-,
Each R ³ is independently H, CN, oxo, C _1-6 alkyl, C _5-14 aryl, CH ₂ C _5-14 aryl, CH ₂ C _3-7 cycloalkyl, C _3-7 cycloalkyl , C _3-7 spirocycloalkyl, C _3-7 cycloalkenyl, C _3-9 heterocycle or C _5-9 heteroaryl, or R ³ is fused together with R ⁶ or R ³ ~ 7 membered ring may be formed, each R ³ group is halo, oxo, C _1-6 alkyl, C _3-7 cycloalkyl, C _1-3 fluoroalkyl, -OC _1-6 alkyl, -C (O) R ⁴ , -C (O) NR ⁴ , -C (O) NHR ⁴ , C _5-14 aryl, C _1-6 heteroalkyl, -B (OH) ₂ , C _3-9 heterocycle, C Optionally substituted by 1 to 4 substituents selected from _5-9 heteroaryl, -C (O) OC _1-6 alkyl, or the two substituents are joined together to form a fused ring, spiro A ring or a bridged ring may be formed, and this condensed ring, spiro ring or bridge Ring may optionally be replaced by R ^4,
R ⁴ is CN, halo, —OC _1-6 alkyl, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-9 heterocycle or C _5-14 aryl,
Each R ⁵ is independently H, C _1-3 alkyl, C _3-6 cycloalkyl, CH ₂ F, CHF ₂ or CF ₃ ;
Each R ⁶ is independently H, oxo, C _1-3 alkyl, C _5-14 aryl, C _3-9 heterocycle, C _5-9 heteroaryl, —C (O) NR ⁴ or —C ( O) NHR ⁴ or both R ⁶ together may contain 2 to 4 carbon atoms and together form a bridged ring system, or R ⁶ is a geminal diester. -C _1-3 alkyl may be represented,
Heterocycle, heteroaryl, heteroalkyl and heteroalkylene each contain 1 to 3 heteroatoms selected from S, N, B or O). The compound of claim 1, wherein R ¹ is C _1-6 alkyl.   3. The compound according to claim 1 or claim 2, wherein W is a bond. The compound according to any one of claims 1 to 3, wherein each R ⁶ is H. R ² is optionally substituted phenyl A compound according to any one of claims 1 to 4. R ² is fluorine, methyl, —CH ₂ CH ₂ CH ₂ O— (wherein the —CH ₂ CH ₂ CH ₂ O— is bonded to an adjacent carbon atom on the phenyl to form a bicyclic ring; Or —NHCH ₂ CH ₂ O— (wherein the —NHCH ₂ CH ₂ O— binds to an adjacent carbon atom on the phenyl to form a bicyclic ring). 6. A compound according to claim 5, which is phenyl substituted by 1 to 4 substituents. Each R ³ is independently C _1-6 alkyl, phenyl, naphthyl, cyclopentyl, cyclohexyl, pyridyl or tetrahydropyranyl, each of which is halogen, C _1-6 alkyl, —OC _1-6 alkyl 7. A compound according to any one of claims 1 to 6, optionally substituted with 1 to 3 substituents selected from C1, _C3 fluoroalkyl or phenyl. Each R ⁵ is methyl, A compound according to any one of claims 1 to 7.   The compound according to any one of claims 1 to 8, wherein X is O. One Y group is NLR ^3, A compound according to any one of claims 1 to 9. Stereochemistry on the carbon XR ¹ is attached is as depicted below, a compound according to any one of claims 1 to 10.

  A pharmaceutically acceptable salt of the compound according to any one of claims 1 to 11.   A pharmaceutical composition comprising the compound or salt according to any one of claims 1 to 12.   14. A method of treating a viral infection in a patient that is at least partially mediated by a virus in the retroviral family of viruses, comprising administering to the patient the composition of claim 13.   15. The method of claim 14, wherein the viral infection is mediated by HIV virus.   13. A compound or salt according to any one of claims 1 to 12 for use in medical therapy.   13. A compound or salt according to any one of claims 1 to 12 for use in the treatment of viral infections in humans.   Use of a compound or salt according to any of claims 1 to 12 in the manufacture of a medicament for use in the treatment of viral infections in humans.